Submissions for variant NM_000335.5(SCN5A):c.373G>C (p.Val125Leu)

dbSNP: rs199473059

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842348	SCV000911300	likely benign	Cardiac arrhythmia	2018-10-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001555910	SCV001011148	likely benign	not provided	2024-05-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000987243	SCV001136493	benign	Brugada syndrome 1	2023-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375549	SCV001572418	likely benign	not specified	2021-04-08	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.373G>C (p.Val125Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 249290 control chromosomes, predominantly at a frequency of 0.0017 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17-fold the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.373G>C has been reported in the literature in individuals with suspected long QT syndrome (e.g.Tester_2005) . These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g. Gutter_2013). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001555910	SCV001777402	likely benign	not provided	2018-07-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28988457, 23805106, 28150151, 29396286, 25351510, 19716085, 15840476)
Ambry Genetics	RCV002345370	SCV002622650	likely benign	Cardiovascular phenotype	2019-12-23	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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058596	SCV000090116	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.