Submissions for variant NM_000335.5(SCN5A):c.1372C>T (p.Arg458Cys)

dbSNP: rs752130196

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000837954	SCV000637080	likely benign	not provided	2023-12-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000837954	SCV000979816	likely benign	not provided	2019-05-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25757662, 30122538, 30677491, 31043699)
Mendelics	RCV000987231	SCV001136480	likely benign	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841455	SCV001357624	uncertain significance	Cardiac arrhythmia	2023-07-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 458 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional assays have shown that this variant may affect sodium channel function but clinical relevance of this finding is not clear (PMID: 25757662). This variant has been reported in an individual affected with sudden infant death (PMID: 25757662) and in an individual suspected to be affected with Brugada syndrome (PMID: 36354768). This variant has been identified in 36/247656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002384103	SCV002697657	likely benign	Cardiovascular phenotype	2020-04-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000837954	SCV004033985	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	SCN5A: BS2
All of Us Research Program, National Institutes of Health	RCV001841455	SCV004825840	uncertain significance	Cardiac arrhythmia	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 458 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional assays have shown that this variant may affect sodium channel function but clinical relevance of this finding is not clear (PMID: 25757662). This variant has been reported in an individual affected with sudden infant death (PMID: 25757662) and in an individual suspected to be affected with Brugada syndrome (PMID: 36354768). This variant has been identified in 36/247656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.