Submissions for variant NM_000335.5(SCN5A):c.3296C>T (p.Ala1099Val)

gnomAD frequency: 0.00021  dbSNP: rs199473192

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183030	SCV000235438	uncertain significance	not provided	2023-11-22	criteria provided, single submitter	clinical testing	Reported in association with LQTS, sudden unexplained death, and cardiomyopathy (Kapplinger et al., 2009; Wang et al., 2014; Pottinger et al., 2020; Rochtus et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 28316956, 24055113, 25637381, 24631775, 28150151, 34426522, 32009526, 29843651, 32449611, 19716085)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183030	SCV000637131	uncertain significance	not provided	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1100 of the SCN5A protein (p.Ala1100Val). This variant is present in population databases (rs199473192, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 19716085, 24631775, 32009526). ClinVar contains an entry for this variant (Variation ID: 67789). 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.
Ambry Genetics	RCV000621290	SCV000736000	likely benign	Cardiovascular phenotype	2023-03-17	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	RCV001842332	SCV001344276	uncertain significance	Cardiac arrhythmia	2022-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1100 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 individual referred for long QT genetic testing (PMID: 19716085) and in an infant affected with sudden death (PMID: 24631775). This variant has been identified in 15/277630 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	RCV002477200	SCV002783867	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	2022-02-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842332	SCV004815259	uncertain significance	Cardiac arrhythmia	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1100 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 individual referred for long QT genetic testing (PMID: 19716085) and in an infant affected with sudden death (PMID: 24631775). This variant has been identified in 15/277630 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058562	SCV000090082	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington	RCV000148851	SCV000190594	uncertain significance	Long QT syndrome	2014-06-01	no assertion criteria provided	research