Submissions for variant NM_000335.5(SCN5A):c.3748G>A (p.Val1250Met)

gnomAD frequency: 0.00038  dbSNP: rs199473600

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154838	SCV000204520	uncertain significance	not specified	2015-05-16	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Val1251Met va riant in SCN5A has not been reported in any other families with DCM. However, it has been identified in a cohort of apparently unaffected African American indiv iduals (1/736 chromosomes; Kapa 2009), as well as in 0.2% (20/10346) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs199473600). Computational prediction tools and conservation analy sis do not provide strong support for or against an impact to the protein. In su mmary, while the clinical significance of the p.Val1251Met variant is uncertain, its frequency suggests that it is more likely to be benign.
GeneDx	RCV000058599	SCV000235603	likely benign	not provided	2021-01-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19841300, 20129283, 15851227, 26746457, 25904541)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058599	SCV000291806	likely benign	not provided	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620228	SCV000737840	likely benign	Cardiovascular phenotype	2019-05-22	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.
Color Diagnostics, LLC DBA Color Health	RCV001842349	SCV001353198	likely benign	Cardiac arrhythmia	2019-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154838	SCV001519589	benign	not specified	2021-03-01	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.3751G>A (p.Val1251Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of 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 0.0002 in 251448 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.3751G>A has been reported in the literature (example Kapa_2009. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia/Brugada/Long QT syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a high throughput patch clamp assay that resulted in re-classification of this variant as benign in accordance with the ACMG classification criteria (example, Glazer_2020). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as benign.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058599	SCV000090119	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300;PMID:20129283).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000058599	SCV000924957	uncertain significance	not provided	2016-06-20	no assertion criteria provided	provider interpretation
Clinical Genetics, Academic Medical Center	RCV000058599	SCV001922810	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000058599	SCV001951593	likely benign	not provided		no assertion criteria provided	clinical testing