Submissions for variant NM_000335.5(SCN5A):c.2923C>T (p.Arg975Trp)

gnomAD frequency: 0.00001  dbSNP: rs41311135

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058537	SCV000545022	uncertain significance	not provided	2024-07-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 975 of the SCN5A protein (p.Arg975Trp). This variant is present in population databases (rs41311135, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 26669661, 32145446; Invitae). ClinVar contains an entry for this variant (Variation ID: 67767). 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 disruptive. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000058537	SCV001153869	uncertain significance	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842321	SCV001346806	uncertain significance	Cardiac arrhythmia	2023-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 975 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 performed for this variant. This variant has been reported in the literature in two related individuals affected with long QT syndrome (PMID: 26669661, 27816319), in an individual referred for long QT syndrome genetic testing (PMID: 20129283), and in two infants affected with sudden death (PMID: 19322600, 32145446). This variant has also been observed in healthy control individuals (PMID: 15851227, 19841300). This variant has been identified in 8/241596 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	RCV002477198	SCV002787136	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	2021-12-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842321	SCV004822745	uncertain significance	Cardiac arrhythmia	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 975 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 performed for this variant. This variant has been reported in the literature in two related individuals affected with long QT syndrome (PMID: 26669661, 27816319), in an individual referred for long QT syndrome genetic testing (PMID: 20129283), and in two infants affected with sudden death (PMID: 19322600, 32145446). This variant has also been observed in healthy control individuals (PMID: 15851227, 19841300). This variant has been identified in 8/241596 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.
Ambry Genetics	RCV004019044	SCV004943829	uncertain significance	Cardiovascular phenotype	2022-07-07	criteria provided, single submitter	clinical testing	The c.2923C>T (p.R975W) alteration is located in exon 17 (coding exon 16) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 2923, causing the arginine (R) at amino acid position 975 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000058537	SCV005198168	uncertain significance	not provided	2023-10-27	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058537	SCV000090057	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:15851227;PMID:19322600;PMID:19841300;PMID:20129283).