Table 2.
Variants assessed as P/LP or VUS/LP in SCD cases with diagnostic structural abnormalities
| Sample ID | Age | Genetic alteration (gene, nucleotide and aminoacidic change) | Variant type | ACMG | ACMG criteria | ClinVar | Variant literature (PMID) | Gene MIM number/cardiac association | ClinGen cardiac association | HP no. phenotype association/gene pathway from GeneCards | Protein |
|---|---|---|---|---|---|---|---|---|---|---|---|
| HCM | |||||||||||
| SCD01 | 26 | n/a | / | / | / | / | / | / | / | / | / |
| SCD03 | 22 |
MYH7 (NM_000257.4): c.4258C > T; p.Arg1420Trp |
missense | LP/P |
PS4 PM1 PM2 PP3 PM5 |
P-HCM | (1–6) | 192600/HCM | HCM/definitive |
0001645-SCD/ Cytoskeleton remodeling: regulation of actin cytoskeleton |
Myosin Heavy Chain 7 |
| SCD14 | 21 | negative | / | / | / | / | / | / | / | / | / |
| SCD15 | 22 | n/a | / | / | / | / | / | / | / | / | / |
| SCD16 | 35 | n/a | / | / | / | / | / | / | / | / | / |
| SCD18 | 20 |
KCNH2 (NM_000238.4): c.1010C > G; p.Thr337Ser |
missense | VUS/LP |
PM2 PP3 PP2 |
u.s.-LQTS | n/a | 613695/LQTS |
LQTS/SQTS/definitive BrS/disputed |
0001645-SCD/ Cardiac conduction: phase3-rapid repolarisation |
Potassium Voltage-Gated Channel (Subfamily H Member 2) |
|
KCNE1 (NM_000219.6): c.95G > A; p.Arg32His |
missense | VUS |
PM2 PM5 |
u.s.-LQTS | (7,8) | 176261/LQTS | LQTS/limited |
0001645-SCD/ Cardiac conduction: phase2-plateau phase; phase3-rapid repolarisation |
Potassium Voltage-Gated Channel (Subfamily E Regulatory Subunit 1) | ||
| SCD27 | 50 |
FBN1 (NM_000138.4): c.979A > G; p.Arg327Gly |
missense | LP/P |
PP3 PP2 PS4 PM2 |
LP-Marfan | (9) | 134797/Marfan Syndrome | Marfan syndrome/ definitive |
0001640-Cardiomegaly; 0001635-Congestive heart failure/ ERK Signaling |
Fibrillin 1 |
| SCD35 | 39 |
SLC4A3 (NM_001326559.2): c.1318G > T; p.Asp440Tyr |
missense | VUS/LP |
PM2 PP3 |
n/a | n/a | 106195/SQT | SQTS/moderate |
0001645-SCD 0001962-Palpitations/ Transport of inorganic cations/anions and amino acids/oligopeptides |
Solute Carrier Family 4 Member 3 (Sodium-independent anion exchanger) |
|
PSEN2 (NM_000447.3): c.506A > G; p.His169Arg |
missense | VUS/LP |
PM2 PP3 PP2 |
u.s | n/a | 600759/DCM | DCM/limited |
0005110-Atrial fibrillation/ 0001279-Syncope ERK Signaling |
Presenilin 2 | ||
| SCD36 | 50 |
SCN10A (NM_001293307.2): c.916G > C; p.Asp306His |
missense | VUS/LP |
PP3 PM2 |
n/a | n/a | 604427/episodic pain/BrS/VT | BrS/disputed |
0001645-SCD/ Cardiac conduction: phase0-rapid depolarisation |
Sodium Voltage-Gated Channel (Alpha Subunit 10) |
|
KCNMA1 (NM_001161352.2): c.3457A > C; p.Lys1153Gln |
missense | VUS/LP |
PP3 PP2 PM2 |
u.s.-epilepsy | n/a | 600150/seizure | n/a |
0030680-Abnormality of cardiovascular system morphology/ Ca2 + activated K + channels |
Potassium Calcium-Activated Channel (Subfamily M Alpha 1) | ||
| SCD37 | 50 |
BAG3 (NM_004281.3): c.67C > T; p.Arg203Trp |
missense | VUS/LP |
PM2 PP3 PM1 |
u.s-DCM/ CMP | n/a | 603883/DCM | DCM/definitive |
0030872-Abnormal cardiac ventricular function/ Cellular responses to stimuli and heat stress |
BAG Cochaperone 3 |
| AC | |||||||||||
| SCD07 | 20 | negative | / | / | / | / | / | / | / | / | / |
| SCD11 | 37 |
RYR2 (NM_001035.3): c.8779C > T; p.Gln2927Ter |
nonsense | LP/P |
PVS1 PM2 |
n/a | n/a | 180902/VA/CPVT |
CPVT/definitive HCM/limited |
0001645-SCD/ Cardiac conduction: ion homeostasis |
Ryanodine Receptor 2 (Calcium channel on sarcoplasmic reticulum) |
| SCD12 | 25 | negative | / | / | / | / | / | / | / | / | / |
| SCD13 | 14 | n/a | / | / | / | / | / | / | / | / | / |
| SCD17 | 45 | negative | / | / | / | / | / | / | / | / | / |
| SCD20 | 50 | negative | / | / | / | / | / | / | / | / | / |
| SCD32 | 29 | DSP (NM_004415.4): c.7000C > T; p.Arg2334Ter | Nonsense | LP/P |
PVS1 PP5 PM2 |
P-AC u.s.-CMP | n/a | 125647/AC |
AC/definitive HCM/disputed |
0001645-SCD/ Signaling by Rho GTPases;Apoptosis |
Desmoplakin |
| DCM | |||||||||||
| SCD10 | 21 | Negative | / | / | / | / | / | / | / | / | / |
AC arrhythmogenic cardiomyopathy, ACMG American College of Medical Genetics, BrS Brugada syndrome, CMP cardiomyopathy, CPVT catecholaminergic polymorphic ventricular tachyarrhythmias, DCM dilated cardiomyopathy, HCM hypertrophic cardiomyopathy, LP likely pathogenic, LQTS long QT syndrome, n/a not available, P pathogenic, SCD sudden cardiac death, SQTS short QT syndrome, u.s. uncertain_significance on ClinVar, VUS/LP variant with unknown significance/likely pathogenic, PVS1 Very Strong—Null variants (nonsense, frameshift, canonical ± 1 or 2 splice sites, initiation codon, single exon or multiexon deletion) in a gene where loss of function is a known mechanism of disease, PM1 Mutational hot spot and/or critical and well-established functional domain, PM2 Absent from controls or at extremely low frequency in Exome Sequencing Project, 1000 Genomes or ExAC, PM5 Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before, PP5 Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation, PP2 Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease, PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product
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