Submissions for variant NM_000335.5(SCN5A):c.1993G>A (p.Ala665Thr)

dbSNP: rs756474485

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766788	SCV000235592	uncertain significance	not provided	2018-08-23	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SCN5A gene. The A665T variant has not been published as pathogenic or been reported as benign to our knowledge. The A665T variant is observed in 18/276636 (0.0065%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the A665T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, although another missense variant at this same residue (A665S) has been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), the pathogenicity of this variant has not been definitively determined. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000766788	SCV000272408	uncertain significance	not provided	2021-11-16	criteria provided, single submitter	clinical testing	The p.Ala665Thr variant in SCN5A has been reported in one individual with sudden unexplained death in infancy (Stroh van Deventer PMID: 29907895). It has also been identified in 0.036% (11/30602) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766788	SCV000637095	uncertain significance	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 665 of the SCN5A protein (p.Ala665Thr). This variant is present in population databases (rs756474485, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 201579). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001842937	SCV000904901	uncertain significance	Cardiac arrhythmia	2023-10-22	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 665 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an infant with sudden death (PMID: 29907895). This variant has been identified in 17/280364 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to 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	RCV002415778	SCV002718599	likely benign	Cardiovascular phenotype	2023-11-16	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.
Fulgent Genetics, Fulgent Genetics	RCV002500546	SCV002814046	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-09-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150058	SCV003838221	uncertain significance	Cardiomyopathy	2022-02-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842937	SCV004839524	uncertain significance	Cardiac arrhythmia	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 665 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an infant with sudden death (PMID: 29907895). This variant has been identified in 17/280364 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to 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.