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. Author manuscript; available in PMC: 2019 Feb 21.
Published in final edited form as: Circulation. 2018 Feb 6;137(6):619–630. doi: 10.1161/CIRCULATIONAHA.117.030142

Classification and Reporting of Potentially Pro-Arrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing

John R Giudicessi 1, Dan Roden 2, Arthur Wilde 3, Michael J Ackerman 4
PMCID: PMC6383807  NIHMSID: NIHMS930372  PMID: 29431662

Abstract

The acquired and congenital forms of long QT syndrome (LQTS) represent two distinct, but clinically and genetically intertwined, disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past two decades, our understanding of the spectrum of genetic variation that i) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, ii) underlies acquired/congenital LQTS-susceptibility, and iii) serves as determinants of QT interval duration in the general population, has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital LQTS. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants with compelling epidemiologic and functional evidence to support a potentially pro-arrhythmic role in patients with congenital and acquired LQTS. As a result, some genetic testing reports may fail to convey the full extent of a patient’s genetic susceptibility for a potentially life threatening arrhythmia to the ordering physician. In this review, we examine the current classification and reporting (or lack thereof) of potentially pro-arrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues.

Keywords: arrhythmia, genetic testing, genetic variation, long QT syndrome, sudden cardiac death

INTRODUCTION

Over the past two decades, the discovery of congenital and acquired (typically drug-induced) long QT syndrome (LQTS)-causative variation in genes that encode components of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins provided an impetus for the development and refinement of clinical genetic tests for LQTS.1, 2 Bolstered by clinically relevant genotype-phenotype correlations and gene-specific risk-stratification/management strategies3, the last decade has seen LQTS genetic testing evolve from initial research laboratory-based endeavors to the current range of clinically useful, commercially-available, and reimbursable genetic tests.4

However, the emergence of next-generation sequencing technologies and ensuing large-scale sequencing efforts has exposed an unexpectedly high frequency of genetic variation within many Mendelian disease-susceptibility genes. Both the canonical and minor LQTS-susceptibility genes are no exception and alarms about “genetic noise” were first sounded in 2003.5, 6 Rare non-synonymous variants in the three primary LQTS-susceptibility genes (KCNQ1, KCNH2, and SCN5A) are seen in ~3%−8% of individuals and make assignment of causation problematic.79 Interpretation of genetic variants in the 14 “minor” LQTS-susceptibibility genes, where much less data on functional consequences are available, is correspondingly more difficult.5, 6, 1012

In an effort to add clarity and uniformity to the classification and reporting of genetic variants in LQTS and other Mendelian disorders, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) released a new set of interpretation and reporting standards in 2015.13 These standards have provided a much needed framework for clinical molecular laboratories tasked with assessing the pathogenicity of putative disease-causative variants indentified in patients with suspected Mendelian disorders. However, the current ACMG/AMP standards specifically avoid guidance on how common genetic variants that may modify the phenotypic manifestations of Mendelian diseases, should be classified and incorporated into diagnostic reports. Such variants have minor allele frequencies (MAF) that far exceed disease prevalence and thus cannot be designated as fully penetrant disease-causing for uncommon monogenic disorders. However, for some of these variants, there is extensive functional and/or epidemiologic evidence to support a role in the modification of disease expressivity and/or the ability to function as independent primary disease-causative alleles under certain conditions. Unfortunately, due to the current interpretation (or misinterpretation) of the 2015 ACMG/AMP by clinical genetic testing laboratories, many “potentially pro-arrhythmic”, but relatively common, genetic variants in established LQTS genes are excluded from diagnostic genetic testing reports, despite a potential role in clinical decision-making.

In light of this pressing issue, this review utilizes LQTS as a prototype to i) examine the conundrum created by the failure of prevailing paradigms to provide adequate guidance regarding the classification and reporting of common genetic variants that may impact clinical decision-making and ii) investigate potential mechanisms by which current ACMG/AMP standards could be modified to better facilitate reporting of these variants in hopes that future genetic testing reports more accurately reflect true genetic risk without introducing an additional source(s) of diagnostic miscues.

Classification and reporting of potentially pro-arrhythmic common variants: the case of p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1

Due to the profound heterogeneity observed with the reporting and classification of variants14, the ACMG/AMP developed the 2015 variant classification and reporting standards to address challenges associated with the increased utilization of next-generation sequencing and inconsistencies in inter-laboratory variant classification.13 In response, many laboratories, including commercial genetic testing companies, that perform clinical genetic testing for Mendelian disorders voluntarily revised their variant classification and reporting schemes to align with the ACMG/AMP guidelines (Table 1).1519

Table 1 |.

Classification and reporting of p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 in commercial long QT syndrome genetic testing

Company* Variant Classification Scheme
Common Variant Reporting
Approach
p.Asp85Asn-
KCNE1
Classification
p.Ser1103Tyr-
SCN5A
Classification
Refs.
Ambry
Genetics
ACMG/AMP guideline-based variant
scorecard (metrics publically available)
Common variants classified as
benign or likely benign not
routinely reported.
Likely benign;
not reported
Likely benign;
not reported

15, 16
Blueprint
Genetics
ACMG/AMP guideline-based variant
scorecard (metrics publically available)
Common variants can be
classified as genetic modifiers
when adequate scientific
evidence exists.
Risk allele;
reported
N/A

15, 17
GeneDx Not publically available Common variants classified as
benign or likely benign are not
reported, but are available on
request.
Not reported Not reported
18
Invitae ACMG/AMP guideline-based variant
scorecard (metrics publically available)
Common variants classified as
benign or likely benign are not
routinely reported, but are
available on request.
Benign;
not reported
Benign;
not reported

15, 19
*

Does not include classification/reporting schemes from those companies that only offer clinical next-generation sequencing/do not offer targeted long QT syndrome and/or cardiac-specific gene panels.

Abbreviations: ACMG, American College of Medical Genetics and Genomics; and AMP, Association for Molecular Pathology.

Of note, the 2015 ACMG/AMP guidelines do not state explicitly that variants classified as “benign” or “likely benign” should be excluded from diagnostic genetic testing reports. In fact, narrative sections for “benign” and “likely benign” variants are even included in sample reports provided by the ACMG/AMP. However, the majority of commercial genetic testing companies have elected to exclude “benign” and “likely benign” variants from their clinical reports (Table 1). Unfortunately, this includes common variants with functionally and clinically significant pro-arrhythmic potential that do not fit cleanly into one of the five ACMG/AMP variant classification categories and often recieve a “benign” or “likely benign” designation based largely on MAF. Consequently and currently, unless ordering health care providers specifically request to be informed of the “benign” and “likely benign” variants present in their patients, they will never know whether a relatively common, but potentially clinically informative common genetic variant is present. As such, the presence of such variants is being withheld from both the patient and the physician who ordered the genetic test. In an effort to ascertain whether relatively common genetic variants with the potential to influence clinical decision-making in LQTS and other Mendelian disorders are “missing in action” due to current variant classification and reporting practices or are “no longer clinically actionable” secondary to a lack of supporting epidemiologic and/or functional evidence, the following paragraphs examine the case for inclusion of two well-studied common variants (p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1) in diagnostic LQTS genetic testing reports.

p.Ser1103Tyr-SCN5A: background noise or potentially pro-arrhythmic common variant in individuals of African descent?

In individuals of African descent, the common SCN5A-encoded Nav1.5 sodium channel variant p.Ser1103Tyr-SCN5A, found in ~10% of African Americans, has been associated with baseline QTc prolongation and a small but persistent risk of arrhythmia/SCD across the age spectrum.2025 Furthermore, in vitro functional characterization by two independent groups demonstrated that p.Ser1103Tyr-SCN5A accentuates the sustained/late sodium current comparable to the electrophysiological phenotype displayed by LQT3-causative p.L613F-SCN5A and p.delQKP1507–1509-SCN5A pathogenic variants.20, 23, 26, 27 However, neither study demonstrated an in vitro or in silico ability of p.Ser1103Tyr-SCN5A to prolong action potential duration in the absence of a “second hit” such as pharmacologic blockade of the rapid-component of the delayed rectifier potassium current (IKr) or respiratory/metabolic acidosis that may arise in the setting of common co-morbid conditions such as sleep apnea, congestive heart failure, and/or chronic kidney disease. Clinically, this epidemiologic and functional evidence suggest that p.Ser1103Tyr-SCN5A is capable of creating a circumstance-dependent, pro-arrhythmic state that may lead to i) sudden infant death syndrome in vulnerable African American infants23, 24 and ii) potentially life-threatening arrhythmias in African American adults recieving QT-prolonging/hypokalemia-predisposing medications20, 25 as well as those with underlying structural heart disease.21, 22

p.Asp85Asn-KCNE1: background noise or potentially pro-arrhythmic common variant in all genetic backgrounds?

The p.Asp85Asn-KCNE1 variant, present in ~1% of individuals worldwide, increases baseline QTc in the general population2830, confers an increased risk of drug-induced torsades de pointes31, 32, modulates the phenotypic severity of primary congenital LQTS (cLQTS)-causative KCNQ1 (LQT1) and KCNH2 (LQT2) pathogenic variants33, 34, and serves as a weak/low penetrant cLQTS-causative variant in Japanese subjects.35 In addition, at least three independent groups have demonstrated that p.Asp85Asn-KCNE1 imparts a LQTS-like loss-of-function in vitro through biophysical effects on the rapid and/or slow components of the phase 3 delayed rectifier repolarizing potassium currents (IK).33, 35, 36 Collectively, the modest cumulative reduction in IK associated with p.Asp85Asn-KCNE1 appears capable of creating a circumstance-dependent, pro-arrhythmic state in the presence of a “second hit” such as i) the use selective IKr blocking medications31, 32, ii) a repolarization reserve-deficient genetic background caused by a primary LQTS pathogenic variant33, 34, or iii) in rare cases, a “genetic cocktail” of multiple common QTc-prolonging genetic variants.

Current classification and reporting of p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 under existing ACMG/AMP guidelines

Although p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 both fail to meet ACMG/AMP criteria for adjudication as cLQTS-causative pathogenic variants (Figure 1)13, in the context of the epidemiologic and functional evidence summarized in Table 220, 23, 31, 33, 35, 36, it is somewhat suprising that the majority of clinical laboratories, including several commercial genetic testing companies, contributing voluntarily to the National Center for Biotechnology’s Clinical Variant (ClinVar) database15 adjudicate p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 as “benign” or “likely benign” (Table 1).

Figure 1 |. Classification of p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1.

Figure 1 |

a) Existing American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) evidence framework organized by the type and strength of evidence needed to support the classification of genetic variants as either benign (left-side) or pathogenic (right-side). Benign and pathogenic criteria fulfilled by p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 are denoted by turquoise and maroon circles, respectively. b) Classification of p.Ser1103Tyr-SCN5A using ACMG/AMP criteria in the context of evidence supporting a role in congenital long QT syndrome (cLQTS) and acquired/drug-induced long QT syndrome (aLQTS). c) Classification of p.Asp85Asn-KCNE1 using ACMG/AMP criteria in the context of evidence supporting a role in cLQTS and drug-induced aLQTS. Additional abbreviations: BA, benign stand-alone; BS, benign strong; BP, FH, family history; benign supporting; LOF, loss-of-function; MAF, minor allele frequency; OR, odds ratio; PP, pathogenic supporting; PS, pathogenic strong; PVS, pathogenic very strong. Adapted from Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424 (2015) with permission from Nature Publishing Group.13

Table 2 |.

Epidemiologic and functional data supporting a conditional role for p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 in acquired and congenital long QT syndrome pathogenesis

Gene dbSNP ID Amino
acid
change
Overall
MAF
(ExAC)
Electrophysiologic phenotype
(in vitro)
QTc
effect
Odds ratio
(aLQTS)
Odds ratio
(cLQTS)
Refs.

SCN5A

rs7626962

S1103Y

0.8%
Increased sustained/late INa
secondary to altered inactivation
gating.

↑ QTc

8.7 (3.2–23.9)

N/A

20, 23

KCNE1

rs1805128

D85N

0.9%
Decreased IKs and/or IKr secondary to
altered activation/inactivation kinetics.

↑ QTc

9.0 (3.5 – 22.9)

3.0 (1.3 – 7.2)#

31, 33, 35, 36
#

Odds ratio calculated from case and control minor frequency allele frequencies provided within the original manuscript by Nishio et al.

Abbreviations: aLQTS, acquired/drug-induced long QT syndrome; cLQTS, congenital long QT syndrome; dbSNP, single nucleotide polymorphism database; ExAC, Exome Aggregation Consortium; MAF, minor allele frequency; QTc, heart-rate corrected QT interval.

Upon closer inspection, it appears that a failure to consider epidemiologic evidence implicating p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 in the pathogenesis of aLQTS at least partially explains this discrepancy. Given that subclinical/concealed cLQTS is often unmasked by non-genetic aLQTS risk factors (i.e. electrolyte abnormalities, QTc-prolonging drugs, etc.) and a small subset of drug-induced aLQTS patients harbor cLQTS-causative pathogenic variants32, 37, 38, the clinical and genetic overlap between aLQTS and cLQTS merits consideration during LQTS variant adjudication. As such, we re-adjudicated p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 in light of additional epidemiologic evidence supporting a role for these variants in aLQTS- and/or SCD-susceptibility (Figure 1b and c). Re-classification of these variants in the context of evidence supporting a role in both aLQTS AND cLQTS resulted in a variant of uncertain significance (VUS) designation that would likely result in the inclusion of p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 on commercial LQTS genetic testing reports (Figure 1b and c). However, even a VUS designation fails to convey the true risk associated with p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 to the ordering healthcare professional.

This is particularly problematic for SCD-predisposing conditions where the clinical context at the time of a patient’s sentinel cardiac event may never be completely understood (i.e. electrolyte derangements, QTc-prolonging medication use, etc.). As such, ordering healthcare professionals deserve to receive as robust of a genetic risk profile as possible, including the presence of potentially pro-arrhythmic common variants such as p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 with the capability to mimic the clinical sequelae of rare cLQTS-causative pathogenic variants under certain conditions. Armed with this genetic information, ordering physicians can then determine whether a given patient’s clinical picture can be explained, in whole or in part, by a “perfect storm” involving the combination of non-genetic risk factors and common variants with pro-arrhythmic potential such as p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1.

Unfortunately, even if broader epidemiologic evidence is used to adjudicate p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1, the current ACMG/AMP framework does not contain a provision that allows for the accurate classification and reporting of potentially pro-arrhythmic common variants. As such, the current ACMG/AMP variant classification and reporting standards need to be amended urgently to provide a mechanism to i) differentiate common variants such as p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 with epidemiologic and functional evidence to suggest a conditional pathogenic contribution from truly ambiguous variants (VUS) and benign variants and ii) encourage the reporting of common variants with the potential to impact clinical decision-making in a standardized fashion that minimizes the risk of misinterpretation and potential diagnostic miscues.

“Functional risk allele”: a necessary addition to existing ACMG/AMP variant classification and reporting standards?

Although current ACMG/AMP guidelines provide little guidance regarding the classification and report of common variants that may contribute to the pathogenesis of Mendelian disorders under certain conditions, they do recommend the reporting of alleles associated with complex/polygenic disease identified incidentally throughout the course of Mendelian disorder genetic testing as “risk alleles” within a distinct “other reportable” category.13 As both p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 underlie QTc duration variability in population-based or genome-wide association studies (GWAS)28, 39, 40, they would both technically qualify for classification as “established/likely risk alleles” under this provision of the 2015 ACMG/AMP guidelines.13 However, a positive GWAS association, regardless of the odds ratio/effect size, should NOT be confused with clinical utility or actionability. In fact, reporting of the ~70 common genetic variants associated with small independent effects on QTc40 in the general population would i) be onerous for genetic testing companies, ii) clutter excessively LQTS genetic testing reports, and iii) be impossible for healthcare professionals to interpret. Therefore, only those common variants with multiple lines of evidence (i.e. ACMG “pathogenic” criteria such as an odds ratio > 5 in multiple case-control studies, well-established functional evidence, etc.) to support a potential conditional contribution to Mendelian disease pathogenesis merit consideration for inclusion on genetic test reports.

One potential interim solution to this conundrum is to create separate “risk allele” and “functional risk allele” designations using criteria within the current ACMG/AMP framework (Table 3). Under these new designations, common and uncommon variants whose MAFs argue against pathogenicity in isolation, but with strong epidemiologic (i.e. an odds ratio >5 in case-control studies consistent with existing pathogenic ACMG/AMP criteria) to suggest a potential pathogenic contribution under certain circumstances, are designated as “risk alleles” (Table 3). Furthermore, those variants, such as p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1, that satisfy epidemiologic criteria for classification as a “risk allele” AND where well-established functional studies display a deleterious effect on gene (i.e. splicing efficiency, transcriptional/translational efficiency, etc.) or protein function (i.e. heterologous expression, in vivo model systems, patient-specific induced pluripotent stem cells, etc.) are eligible for elevation to the designation of “functional risk allele” in general and in the context of heritable cardiac arrhythmia syndrome genetic testing, a “potentially pro-arrhythmic functional risk allele” (Table 3). Lastly, due to ethnic-specific genetic backgrounds, use of divergent in vivo model organisms, and/or variable in vitro experimental conditions, as illustrated above, circumstances are bound to arise where discrepant epidemiologic and/or functional evidence exists for a given genetic variant. Unfortunately, no formal guidelines exist to help variant adjudicators or ordering healthcare professionals resolve discrepant clinical or functional data. However, in the event discrepancies cannot be readily explained (e.g. variable accessory subunit co-expression, established difference in endogenous/background current expression between cell lines, etc.), the use of a third designation “possible risk allele – weak/conflicting evidence” can be considered to alert ordering healthcare professionals to the presence of a relatively common variant with some evidence, albeit weak, to suggest that the variant may not be completely benign. Regardless of designation, to avoid potentially harmful diagnostic miscues, variants meeting these criteria should be reported under a separate “Risk Allele” or “Other Reportable” category with a boiler plate disclaimer such as “This variant is NOT a self-sufficient, disease-causative mutation in isolation. However, in the setting of either disease-causative mutations or acquired risk factors, the presence of this risk allele can potentially increase the patient’s risk of disease.”

Table 3 |.

Rules for classifying common sequence variants with a potential conditional contribution to Mendelian disease pathogenesis using existing ACMG/AMP variant classification criteria

Functional risk allele Strong epidemiologic (PS3) and functional (PS4) evidence to suggest a pathogenic
contribution but minor allele frequency ≥ disease prevalence (BS1) or ≥ 5% in public
exomes (BA1)
Risk allele Strong epidemiologic evidence to suggest a pathogenic contribution (PS3) but minor
allele frequency ≥ disease prevalence (BS1) or ≥ 5% in public exomes (BA1)
Possible risk allele –
weak/conflicting evidence
Conflicting and/or weak evidence regarding the existence of ≥ 1 pathogenic strong
criteria (PS3 or PS4) but minor allele frequency ≥ disease prevalence (BS1) or ≥ 5% in
public exomes (BA1)

Abbreviations: ACMG, American College of Medical Genetics and Genomics; AMP, Association for Molecular Pathology; BA, benign stand-alone; BS, benign strong; and PS, pathogenic strong.

As applied to relatively common amino acid-altering variants in major channelopathy-susceptibly genes likely to be encountered in clinical practice (Table 4)4163 and outlined in Figure 264, this classification scheme provides a mechanism to bring potentially clinically meaningful variants, including p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1, that might otherwise be ignored or perpetually stuck erroneously with a “VUS” designation to the attention of ordering healthcare professionals. Unfortunately, due to a reliance on existing ACMG/AMP criteria, these designations are anticipated to be overly conservative and fail to account for 1) established channelopathy-associated “genetic modifiers” such as p.His558Arg-SCN5A that may confer either a “protective” or “deleterious” effect on the phenotypic severity associated with a primary disease-causative pathogenic variant, 2) composite effect(s) of >1 relatively common genetic variants, such as p.Ala572Asp-SCN5A plus p.His558Arg-SCN5A or p.Val1951Leu-SCN5A with p.delGln1077-SCN5A (Table 4), that produce a synergistic effect under a specific genomic context [i.e. on the same (cis) or on the opposite allelle (trans) relative to each other], 3) the underappreciated ability of coding region variants to impact gene function/expression independent of protein-level effects (i.e. codon bias influencing translational efficiency, epigenetic regulation, splicing efficiency, etc.), and/or 4) variants that reside outside protein coding regions and canonical splice sites. This is due, in part, to the lack of criteria within the existing ACMG/AMP guidelines to account for these issues and represents an area where future disease-specific guidelines could improve upon the existing ACMG/AMP variant classification standards.

Table 4 |.

Current and amended classification of non-synonymous variants in KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 with a minor allele frequency ≥ 0.1% in public exomes.

Variant ExAC
MAF
Functional
Evidence
Epidemiologic
Evidence
SIFT/PolyPhen
Prediction
Current ACMG
Classification
Amended ACMG
Classification
Refs.
p.Lys393Asn-KCNQ1 0.1% N/A N/A Benign/tolerated Likely benign Likely benign N/A
p.Pro408Ala-KCNQ1 0.1% N/A N/A Benign/tolerated Likely benign Likely benign N/A
p.Pro448Arg-KCNQ1 0.8% N/A N/A Benign/tolerated Likely benign Likely benign N/A
p.Gly643Ser-KCNQ1 2% N/A N/A Benign/tolerated Likely benign Likely benign N/A
p.Val648Ile-KCNQ1 0.4% N/A N/A Benign/tolerated Likely benign Likely benign N/A
p.Arg148Trp-KCNH2 0.1% N/A N/A Benign/tolerated Likely benign Likely benign N/A
p.Pro347Ser-KCNH2 0.2% Wild-type N/A Benign/tolerated Benign Benign 41
p.Lys897Thr-KCNH2 18.7% SQTS-like IKr
GoF/LQTS-like IKr
LoF
Over-represented in
TdP in acute MI/Not
over-represent in
aLQTS
Benign/tolerated Benign Possible risk
allele – CE§
4147
p.Arg1047Leu-KCNH2 0.8% Wild-type/modest
LQTS-like IKr LoF
Over-represented in
dofetilide-associated
TdP
Possibly
damaging/tolerated
Likely benign Possible risk
allele – CE/WE
22, 41, 45
p.Arg34Cys-SCN5A 1.0% Wild-type N/A Possibly
damaging/tolerated
Benign Benign 48
p.Leu461Val-SCN5A 0.1% N/A N/A Benign/tolerated Likely benign Likely benign N/A
p.Arg481Trp-SCN5A 0.1% LQTS-like INa GoF N/A Possibly
damaging/deleterio
us
Likely benign Possible risk
allele - WE
48
p.Ser524Tyr-SCN5A 0.5% BrS-like INa LoF N/A Possibly
damaging/tolerated
Likely benign Possible risk
allele - WE
48, 49
p.Ala572Asp-SCN5A 0.4% Wild-type/LQTS-
like INa GoF*
Not over-represented
in disease
Benign/tolerated Likely benign Possible risk
allele – CE
5052
p.His558Arg-SCN5A 22.2% SCN5A variant-
specific modulatory
effects on Nav1.5
trafficking/biophysi
cs
Not over-represented
in disease.
Benign/tolerated Benign Benign§ 5357
p.Pro1090Leu-SCN5A 0.2% LQTS-like INa GoF N/A Benign/tolerated Likely benign Possible risk
allele - WE
48
p.Ser1103Tyr-SCN5A 0.8% LQTS-like INa GoF Over-represented in
aLQTS, SCD in SHD,
and SIDS
Possibly
damaging/deleterio
us
Benign Functional risk
allele
20, 23
p.Arg1193Gln-SCN5A 0.6% Mixed INa LoF/GoF Over-represented in
symptomatic BrS1
cases with appropriate
ICD shocks.
Benign/tolerated Likely benign Functional risk
allele
48, 58, 59
p.Val1951Leu-SCN5A 0.5% Wild-type/LQTS-
like INa GoF*
N/A Benign/tolerated Likely benign Possible risk
allele – CE
48, 60, 61
p.Phe2004Leu-SCN5A 0.2% Conflicting
evidence
Not over-represented
in disease
Benign/tolerated Likely benign Possible risk
allele – CE
60, 62
p.Pro2006Ala-SCN5A 0.1% Wild-type/LQTS-
like INa GoF*
N/A Benign/tolerated Likely benign Possible risk
allele – CE
60, 61
p.Ser38Gly-KCNE1 65% N/A N/A Benign/tolerated Benign Benign N/A
p.Asp85Asn-KCNE1 0.9% LQTS-like IKr
and/or IKs LoF
Over-represented in
aLQTS
Benign/deleterious Likely benign Functional risk
allele
31, 33,
35, 36
p.Thr8Ala-KCNE2 0.4% Increased IKr during
premature stimulus
N/A Probably
damaging/deleterio
us
Likely benign Possible risk
allele – WE
63
p.Gln9Glu-KCNE2 0.2% Increased IKr during
premature stimulus
N/A Benign/tolerated Likely benign Possible risk
allele – WE
63
*

The association of a functional phenotype with these variants may be dependent on genomic context (p.Ala572Asp-SCN5A with p.His558Arg, p.Val1951Leu-SCN5A with p.delGln1077-SCN5A, and p.Pro2006Ala-SCN5A with p.His558Arg-SCN5A).

At a minimum, the authors recommend reporting of these variants under a distinct “Risk Allele” or “Other Reportable” category with a disclaimer such as “This variant is NOT a self-sufficient disease-causative mutation in isolation. However, in the setting of either disease-causative mutations or acquired risk factors, the presence of this particular variant can potentially increase the patient’s risk of disease expressivity.”

At present, there is not substantive epidemiologic evidence to support a role for variants classified as “possible risk allele – conflicting/weak evidence” in clinical decision-making. However, should these variants be included in future genetic testing reports (e.g. as “benign/likely benign” variants), every effort should be made to alert ordering healthcare providers of the potential deleterious functional effect(s) associated with these variants and the genomic context, if any, where this deleterious functional effect is most likely to be observed (e.g. co-existence of p.Ala572Asp-SCN5A with p.His558Arg-SCN5A).

§

Due to limitations associated with the current ACMG/AMP classification criteria, it is anticipated that variants that primarily act as genetic modifiers will continue to be classified as benign/likely benign. Until revised/formal guidelines are available, inclusion of variants such as SCN5A-His558Arg that primarily act as modifiers should be evaluated on a case-by-case basis and potentially listed as “possible genetic modifiers” if substantive evidence exists to support such a role.

Abbreviations: ACMG, American College of Medical Genetics and Genomics; aLQTS, acquired long QT syndrome; BrS, Brugada syndrome; CE, conflicting evidence; ExAC, Exome Aggregation Consortium; GoF, gain-of-function; ICD, implantable cardioverter-defibrillator; IKr, rapid component of the delayed-rectifier potassium current; INa, inward depolarizing sodium current; LoF, loss-of-function; LQTS, long QT syndrome; MAF, minor allele frequency; MI, myocardial infarction; TdP, torsades de pointes; SCD, sudden cardiac death; SHD, structural heart disease; SQTS, short QT syndrome; and WE, weak evidence.

Figure 2 |. Rational approach to the classification of rare and common genetic variants.

Figure 2 |

Light gray boxes denote basic considerations pertaining to the initiation of genetic testing. Light orange boxes denote key steps in the classification of rare, rare common, and common genetic variants based on existing American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines highlighting how existing benign and pathogenic criteria can be utilized to identify potential rare common conditional variants. Green boxes denote basic considerations pertaining to the identification of a rare variant of unknown/uncertain significance that currently lacks sufficient evidence to classify as either benign or pathogenic. *Given a substantial clinical and genetic overlap, evidence supporting a role in congenital and acquired LQTS should be considered when classifying potential LQTS risk alleles. Denotes variant designations that merit inclusion on LQTS genetic testing reports under distinct “primary findings” (pathogenic and variants of uncertain significance) or “other reportable” (functional risk alleles) categories. Adapted from Giudicessi et al. Precision Cardiovascular Medicine: State of Genetic Testing. Mayo Clinic Proceedings 92(4):642–662 (2017) with permission from Elsevier.64

That said, inclusion of “potentially pro-arrhythmic common variants” such as p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 within a distinct category of the genetic testing report would allow for the communication of variants that may influence clinical-decision making without increasing the risk of diagnostic miscues secondary to the mis- or over-interpretation of these findings. When properly informed of the presence of one of these aforementioned “functional risk alleles”, avoiding QT prolonging medications (www.crediblemeds.org) may be a simple and yet life-saving preventative measure. Accordingly, an updated classification scheme with reporting of these “risk alleles” and “functional risk alleles” is needed urgently. Such an updated classification scheme could be beneficial in not only in LQTS and other SCD-predisposing cardiac channelopathies decision-making (e.g. risk-stratification, selection of anti-arrhythmic drugs, etc.), but also in other Mendelian disorders.

Beyond long QT syndrome: functional risk alleles and non-channelopathic Mendelian heart disorders

As illustrated in Table 2, the number of “risk alleles” and “functional risk alleles” potentially unearthed, but not currently reported, during the course of genetic testing for LQTS and other SCD-predisposing cardiac channelopathies extends beyond p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1. Given the number of channelopathy/QT interval GWAS and relative ease by which the functional impact of non-synonymous genetic variation in cardiac ion channel genes can be assessed in vitro, these findings should come as little surprise. However, it would be presumptious to assume that the common variant reporting issue exemplified by p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 is confined to the cardiac channelopathies.

In fact, evidence already exists to suggest a similar common variant phenomenon may, albeit to a lesser extent, impact non-channelopathic genetic heart disorders. Within the cardiomyopathies, the strongest example involves a common 25-bp deletion in intron 32 of MYBPC3, present in ~4% of South Asians, that leads to exon 33 skipping and increased risk of late-onset hypertrophic cardiomypathy.65 Although unlikely to be encountered using the sequencing approaches commonly employed in commercial genetic testing today, this example highlights the potential of functional common variants, located throughout the genome, to contribute to non-channelopathic genetic heart disorders and reinforces the danger of over-looking the potential clinical relevance of common variants on the basis of MAF alone.

In addition, common functional non-synonymous variants in familial hypercholesterolemia-susceptibility genes, most notably p.Gly116Ser-LDLR present in ~10% of Inuit individuals66, strongly influence plasma low-density lipoprotein levels and/or result in a non-classical familial hypercholesterolemia (FH) phenotype. Similar to the African-specific p.Ser1103Tyr-SCN5A LQTS functional risk allele, a strict application of the 2015 ACMG/AMP guidelines would classify the Inuit-specific p.Gly116Ser-LDLR familial hypercholesterolemia functional risk allele as “benign” on the basis of MAF alone.

As additional Mendelian GWAS and large scale genetic modifier studies are undertaken, our understanding of the contribution of common variants to the genetic architecture of Mendelian genetic heart disorders is anticipated to grow. When coupled with the ongoing shift from disease-specific genetic testing to relatively non-specific pan-cardiac gene panels and clinical whole exome/genome sequencing, the likelihood a common, but potentially clinically relevant, genetic variant in Mendelian disease-susceptibility genes is encountered is expected to increase exponentially. As such, the above examples in the cardiac channelopathies, cardiomyopathies, and familial hypercholesterolemia serve to further underscore the acute need to develop and implement mechanisms to delineate so-called “risk alleles” in Mendelian disease-susceptibility genes from variants that are truly benign or of uncertain signficance.

CONCLUSION

Although the current ACMG/AMP variant classification and reporting standards provide a solid foundation, the general nature of these guidelines were not intended, nor should they be presumed, to account for the intricacies and idiosyncrasies associated with specific disorders. As illustrated in this review, the application of a “one size fits all” approach to variant interpretation has likely resulted in genetic tests that sub-optimally reflect a patient’s true underlying genetic risk of potentially fatal cardiac arrhythmias. Ultimately, the general ACMG/AMP framework needs to be adapted and tailored to fit LQTS and other genetic heart disorders through the development of expert consensus variant guidelines regarding the classification and reporting of rare and common genetic variants. However, until such documents can be drafted and thoroughly vetted, the “risk allele” and “functional risk allele” designations put forward in this review may serve as the best, albeit imperfect, stop-gap measure designed to ensure that ordering healthcare professionals are informed of common variants such as p.Ser1103Tyr-SCN5A and p.Asp85Asn-KCNE1 encounted during disease-specific, pan-cardiac, and clinical whole exome genetic testing and afforded every opportunity to institute the simple interventions [i.e. avoidance of QTc prolonging medications (www.crediblemeds.org)67, judicious use of anti-pyretics, potassium supplementation, etc.) needed to mitigate the small but increased risk for sudden death these variants confer.

Supplementary Material

Fig 1 Permission
Fig 2 Permission

Acknowledgments

Funding Sources: This work was supported by the Windland Smith Rice Sudden Comprehensive Sudden Cardiac Death Program (to Dr. Ackerman). Dr. Giudicessi thanks the Mayo Clinic Cardiovascular Diseases Fellowship and Clinician Investigator Training Programs for fostering an outstanding environment for physician-scientist training.

Abbreviations:

ACMG

American College of Medical Genetics and Genomics

aLQTS

acquired long QT syndrome

AMP

Association for Molecular Pathology

cLQTS

congenital long QT syndrome

IK

delayed rectifying potassium current

LQTS

long QT syndrome

MAF

minor allele frequency

QTc

heart-rate corrected QT interval

SCD

sudden cardiac death

VUS

variant of uncertain significance

Footnotes

Conflict of Interest Disclosures: Dr. Ackerman is a consultant for Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St. Jude Medical. From 2004 to 2016, M.J.A. and Mayo Clinic received sales-based royalties from Transgenomic for their FAMILION-LQTS and FAMILION-CPVT genetic tests. However, none of these entities participated in this study. Drs. Giudicessi, Roden, and Wilde declare no conflicts.

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