Submissions for variant NM_000335.5(SCN5A):c.856G>T (p.Ala286Ser)

gnomAD frequency: 0.00089  dbSNP: rs61746118

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154846	SCV000204528	likely benign	not specified	2018-04-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000154846	SCV000235293	likely benign	not specified	2017-05-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000058852	SCV000291836	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618432	SCV000737395	likely benign	Cardiovascular phenotype	2018-12-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154846	SCV000918196	likely benign	not specified	2018-09-17	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.856G>T (p.Ala286Ser) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 279948 control chromosomes, predominantly within the African subpopulation, at a frequency of 0.0029, in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 29-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 a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.856G>T in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Athena Diagnostics	RCV000058852	SCV001145508	benign	not provided	2018-09-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842413	SCV001343047	likely benign	Cardiac arrhythmia	2018-12-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537263	SCV004740216	likely benign	SCN5A-related disorder	2022-02-03	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058852	SCV000090372	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300;PMID:20129283).
Clinical Genetics, Academic Medical Center	RCV000154846	SCV001926079	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000058852	SCV001931085	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000058852	SCV001971253	likely benign	not provided		no assertion criteria provided	clinical testing