Table 1 Pathogenic and likely pathogenic cardiac channelopathy variants as per ACMG/AMP guidelines
Gene | cDNA change | AA change | dbSNP ID | Functional or segregation evidence | ClinVar | ACMG/AMP attributes | ACMG/AMP classification |
|---|---|---|---|---|---|---|---|
KCND3 | c.1348C > T | p.L450F | rs150401343 | Gain of function of KV4.3/KChIP2‑encoded channels (PMID: 26016905) | Conflicting_interpretations_of_pathogenicity | PS3PM2PP2BP4 | Likely Pathogenic(II) |
SCN5A | c.6046G > A | p.V2016M | rs762981322 | Loss of function by reduced cell surface expression and peak Na+ current (PMID: 24895455 and PMID: 26282245) and gain of function by protein kinase A or C activation (PMID: 26282245) | Conflicting_interpretations_of_pathogenicity | PS3PM2PP3 | Likely Pathogenic(II) |
KCNH2 | c.2467C > T | p.R823W | rs199473538 | Trafficking defect (PMID: 16432067) and Failure to return to normal repolarisation (PMID: 23303164) | Pathogenic/likely_pathogenic | PS3PM1PM2PP3PP5BP1 | Pathogenic(IIIb) |
KCNE3 | c.49G > A | p.V17M | rs773287275 | Gain of function on Kv4.3/KCNE3 and Kv11.1/KCNE3 generated currents (PMID: 18209471) | Uncertain_significance | PS3PM2PP3 | Likely Pathogenic(II) |
SCN3B | c.328G > A | p.V110I | rs147205617 | Loss of function by reducing sodium current (23257389) | Conflicting_interpretations_of_pathogenicity | PS3PM1PP3 | Likely Pathogenic(II) |
CACNA1C | c.2573G > A | p.R858H | rs786205753 | Gain of function on Ica (PMID: 24728418) | Pathogenic/likely_pathogenic | PS3PM2PP2PP3PP5 | Likely Pathogenic(II) |
KCNE2 | c.170T > C | p.I57T | rs74315448 | Gain of function of Ito (PMID: 20042375), loss of function of Iks (PMID: 11101505), loss of function of Ikr (PMID: 10219239) | Conflicting_interpretations_of_pathogenicity | PS3PM1PP2PP3 | Likely Pathogenic(II) |
KCND3 | c.1649G > A | p.R550H | rs151164490 | NA | Uncertain_significance | PM1PM2PP2PP3 | Likely Pathogenic(V) |
KCND3 | c.325G > C$ | p.E109Q | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
RYR2 | c.356 T > C$ | p.I119T | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
RYR2 | c.745 T > C$ | p.S249P | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
RYR2 | c.892C > T | p.R298C | rs551099887 | NA | Conflicting_interpretations_of_pathogenicity | PM1PM2PP2PP3 | Likely Pathogenic(V) |
RYR2 | c.1396C > T$ | p.P466S | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
RYR2 | c.1910 T > G$ | p.L637R | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
RYR2 | c.1940G > A | p.R647H | rs766330093 | NA | Uncertain_significance | PM1PM2PP2PP3 | Likely Pathogenic(V) |
RYR2 | c.4388G > A | p.R1463H | rs753707154 | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
RYR2 | c.4531G > T | p.V1511L | NA | NA | Uncertain_significance | PM1PM2PP2PP3 | Likely Pathogenic(V) |
RYR2 | c.6367C > T | p.L2123F | rs1060500159 | NA | Uncertain_significance | PM1PM2PP2PP3 | Likely Pathogenic(V) |
RYR2 | c.11758C > A$ | p.L3920I | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
RYR2 | c.13526 T > C | p.V4509A | NA | NA | Uncertain_significance | PM1PM2PP2PP3 | Likely Pathogenic(V) |
CAV3 | c.244G > T$ | p.V82F | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
KCNQ1 | c.1570G > T$ | p.V524L | NA | NA | NA | PM1PM2PM5BP4 | Likely Pathogenic(IV) |
CACNA1C | c.1914C > A | p.S638R | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
CACNA1C | c.2813 T > C | p.I938T | rs377165829 | NA | Uncertain_significance | PM1PM2PP2PP3 | Likely Pathogenic(V) |
CACNA1C | c.2837 T > C | p.I946T | rs747728381 | NA | Uncertain_significance | PM1PM2PP2PP3 | Likely Pathogenic(V) |
CACNA1C | c.3200C > T | p.A1067V | rs750998195 | NA | Conflicting_interpretations_of_pathogenicity | PM1PM2PP2PP3 | Likely Pathogenic(V) |
CACNA1C | c.3691C > T | p.L1231F | rs766971426 | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
CACNA1C | c.4819C > T | p.P1607S | rs745938574 | NA | Uncertain_significance | PM1PM2PP2PP3 | Likely Pathogenic(V) |
CACNA1C | c.5270G > T | p.S1757I | rs753388569 | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
CACNA1C | c.5684G > A | p.R1895Q | rs753954220 | NA | Uncertain_significance | PM2PP2PP3PM1 | Likely Pathogenic(V) |
ABCC9 | c.2474C > T | p.A825V | rs964127282 | NA | Uncertain_significance | PM1PM2PP2PP3 | Likely Pathogenic(V) |
ABCC9 | c.1318C > G$ | p.Q440E | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
KCNJ2 | c.208G > C$ | p.A70P | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
KCNJ2 | c.817A > G$ | p.I273V | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
KCNE2 | c.131A > G$ | p.E44G | NA | NA | NA | PM1PM2PP2PP3 | Likely Pathogenic(V) |
KCNE2 | c.229C > T | p.R77W | rs141423405 | No effect on Ikr (PMID: 17275752) | Uncertain_significance | PM1PM2PP2PP3BS3 | Likely Pathogenic(V) |