Submissions for variant NM_000335.5(SCN5A):c.1109C>T (p.Thr370Met)

dbSNP: rs199473099

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001841770	SCV001356353	uncertain significance	Cardiac arrhythmia	2020-11-10	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 370 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 been reported in individuals affected with long QT syndrome (PMID: 18508782, 23631430, 28438721, 31245010, 32383558), and in an individual affected with sudden adult death (PMID: 16712702). One of these individuals also carried a pathogenic variant in the KCNQ1 gene (PMID: 23631430), suggesting that this variant may not be the primary cause of disease observed in the proband. In one family, this variant has been shown to not segregate with long QT syndrome (Sanchez et al., 2014). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003541161	SCV001412818	uncertain significance	not provided	2021-06-04	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with clinical features of long QT syndrome or who suffered sudden death (PMID: 16712702, 18508782, 19716085, 23631430, 28438721). However, in one of these individuals pathogenic allele[s] were also identified in KCNQ1, which suggests that this c.1109C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 67636). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with methionine at codon 370 of the SCN5A protein (p.Thr370Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256850	SCV001433336	uncertain significance	Dilated cardiomyopathy 1A	2019-03-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162453	SCV003903551	uncertain significance	Cardiovascular phenotype	2023-02-15	criteria provided, single submitter	clinical testing	The p.T370M variant (also known as c.1109C>T), located in coding exon 8 of the SCN5A gene, results from a C to T substitution at nucleotide position 1109. The threonine at codon 370 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in subjects with features of long QT syndrome and in sudden death individuals (Hofman-Bang J et al. Clin Genet, 2006 Jun;69:504-11; Behr ER et al. Eur Heart J, 2008 Jul;29:1670-80; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Al-Hassnan ZN et al. Heart Rhythm, 2017 Aug;14:1191-1199; Webster G et al. JAMA Cardiol, 2021 Nov;6:1247-1256). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224130	SCV003920449	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	2021-03-30	criteria provided, single submitter	clinical testing	SCN5A NM_198056.2 exon 9 p.Thr370Met (c.1109C>T): This variant has been reported in the literature in at least 3 individuals with features of Long QT syndrome and sudden death (Hofman-Bang 2006 PMID:16712792, Behr 2008 PMID:1850878, Kapplinger 2009 PMID:19716085, Lieve 2013 PMID:23631430). Of note, one of these individuals also carried an additional disease causing variant in KCNQ1 (p.Gly168Arg). This variant is not present in large control databases but is present in ClinVar (Variation ID:67636). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058393	SCV000089913	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:16712702;PMID:18508782;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678842	SCV000805031	uncertain significance	Long QT syndrome	2015-07-30	no assertion criteria provided	clinical testing