Table 3.
Variants assessed as P/LP or VUS/LP in SCD cases with non-diagnostic autopsy findings
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Mild fatty replacement | |||||||||||
| SCD19 | 40 | CACNA1C (NM_000719.7): c.2558 T > C; p.Met853Thr | missense | VUS/LP |
PM2 PM1 PP3 PP2 |
u.s.-LQTS | n/a | 114205/BRs/LQTS |
LQTS/moderate BrS/SQTS/disputed |
0001645-SCD/ Cardiac conduction: phase 2-plateau phase |
Calcium Voltage-Gated Channel (Subunit Alpha1 C) |
| SCD24 | 31 | negative | / | / | / | / | / | / | / | / | / |
| SCD26 | 23 | ATP1A2 (NM_000702.4): c.1352A > C; p.Glu451Ala | missense | VUS/LP |
PP3 PP2 PM2 |
n/a | n/a | 182340/n/a | n/a |
0011675-Arrhythmia/ Cardiac conduction: ion homeostasis; ion transport by P-type ATPases |
ATPase Na+/K+ Transporting Subunit Alpha 2 |
| SCD33 | 50 | SNTA1 (NM_003098.3): c.583delC; p.Leu195Phefs*23 | frameshift | LP |
PVS1 PM2 |
n/a | n/a | 612955/LQTS | LQTS/disputed |
0001645-SCD/ NGF Pathway |
Syntrophin Alpha 1 |
| Mitral valve prolapse | |||||||||||
| SCD09 | 25 | n/a | / | / | / | / | / | / | / | / | / |
| SCD21 | 29 | TGFB2 (NM_001135599.3): c.1312 T > C; p.Ser410Pro | missense | LP |
PP3 PM2 |
n/a | n/a | 190220/Loeys-Dietz syndrome | Loeys-Dietz syndrome/definitive |
0001654-Abnormal heart valve morphology/ ERK Signaling |
Transforming growth factor beta 2 |
|
SCN5A (NM_001160161.2): c.1820G > A; p.Gly607Asp |
missense | VUS |
PM2 PP2 |
n/a | n/a | 600163/BrS/LQTS |
Brs/LQTS/DCM/ definitive AC/limited CPVT/SQTS/ disputed |
0001645-SCD/ Cardiac conduction: phase0-rapid depolarisation |
Sodium Voltage-Gated Channel (Alpha Subunit 5) | ||
| Small foci of fibrosis | |||||||||||
| SCD23 | 34 |
TTN (NM_001267550.2): c.69936C > G; p.Tyr23312Ter |
nonsense | P |
PVS1 PM2 |
n/a | n/a | 188840/DCM/HCM |
DCM/definitive HCM/AC/limited |
0001645-SCD/ Striated muscle contraction; cardiac conduction |
Titin |
| SCD30 | 40 | negative | / | / | / | / | / | / | / | / | / |
| Slightly dilated chambers | |||||||||||
| SCD29 | 42 |
LAMA4 (NM_002290.4): c.719-2A > G; |
splicing | LP |
PVS1 PM2 |
u.s-DCM | (1) | 600133/DCM | DCM/limited |
0001644-DCM; 0012664-Reduced left ventricular ejection fraction/ ERK Signaling |
Laminin (Subunit Alpha 4) |
|
CDH2 (NM_001792.4): c.1729G > C; p.Ala577Pro |
missense | VUS/LP |
PM2 PP3 |
u.s | n/a | 114020/AC | AC/limited |
0004756-Ventricular tachycardia; 0011675-Arrhythmia/ Cell junction organization; ERK Signaling |
Cadherin 2 | ||
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, PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product, 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
1.Verdonschot JAJ, Hazebroek MR, Krapels IPC, Henkens MTHM, Raafs A, Wang P, et al. Implications of Genetic Testing in Dilated Cardiomyopathy. Circ Genom Precis Med. 2020 Oct;13(5):476–87