Submissions for variant NM_000335.5(SCN5A):c.5842G>A (p.Ala1948Thr)

gnomAD frequency: 0.00002  dbSNP: rs199473330

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183134	SCV000235547	uncertain significance	not provided	2016-08-15	criteria provided, single submitter	clinical testing	The A1949T variant of uncertain significance in the SCN5A gene has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A1949T 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. Additionally, this substitution occurs at a position that is conserved across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810984	SCV000951226	uncertain significance	Brugada syndrome	2022-09-01	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 1949 of the SCN5A protein (p.Ala1949Thr). This variant is present in population databases (rs199473330, gnomAD 0.01%). 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: 201545). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	RCV001842929	SCV001348294	uncertain significance	Cardiac arrhythmia	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1949 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 7/247058 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002492818	SCV002776622	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	2021-10-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842929	SCV004829588	uncertain significance	Cardiac arrhythmia	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1949 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 7/247058 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000183134	SCV005198155	uncertain significance	not provided	2023-11-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004539708	SCV004788089	uncertain significance	SCN5A-related disorder	2023-11-22	no assertion criteria provided	clinical testing	The SCN5A c.5845G>A variant is predicted to result in the amino acid substitution p.Ala1949Thr. This variant was reported in the heterozygous state in an individual with familial coronary artery disease (Table S3A, Salfati et al. 2019. PubMed ID: 31847883). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.