Submissions for variant NM_000335.5(SCN5A):c.3951G>A (p.Glu1317=)

gnomAD frequency: 0.00009  dbSNP: rs769473892

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000248843	SCV000306545	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV001705342	SCV000515374	likely benign	not provided	2018-12-20	criteria provided, single submitter	clinical testing
Invitae	RCV001705342	SCV000830113	likely benign	not provided	2024-01-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000248843	SCV000920191	benign	not specified	2018-04-16	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.3954G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 3.3e-05 in 267386 control chromosomes (gnomAD). The observed variant frequency is approximately 1-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. To our knowledge, no occurrence of c.3954G>A in individuals affected with Cardiomyopathy and/or Arrhythmia, and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000248843	SCV001160192	likely benign	not specified	2019-04-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001843023	SCV001358812	likely benign	Cardiac arrhythmia	2018-11-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002356343	SCV002619489	likely benign	Cardiovascular phenotype	2019-02-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.