Submissions for variant NM_000335.5(SCN5A):c.2365G>A (p.Val789Ile)

gnomAD frequency: 0.00002  dbSNP: rs199473159

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454526	SCV000540291	uncertain significance	not specified	2016-10-20	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1/2111 probands - similar frequency to controls; GET-Evidence classifies as LB
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058498	SCV000819960	uncertain significance	Brugada syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 789 of the SCN5A protein (p.Val789Ile). This variant is present in population databases (rs199473159, gnomAD 0.01%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 25904541). ClinVar contains an entry for this variant (Variation ID: 67729). 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV002483111	SCV002783887	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	2022-02-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162456	SCV003903584	uncertain significance	Cardiovascular phenotype	2023-08-14	criteria provided, single submitter	clinical testing	The p.V789I variant (also known as c.2365G>A), located in coding exon 14 of the SCN5A gene, results from a G to A substitution at nucleotide position 2365. The valine at codon 789 is replaced by isoleucine, an amino acid with highly similar properties. This variant was detected in a suspected Brugada syndrome cohort that was referred for genetic testing; however, clinical details were not provided (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). 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.
Color Diagnostics, LLC DBA Color Health	RCV003591668	SCV004361685	uncertain significance	Cardiac arrhythmia	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 789 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 14/249170 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.
All of Us Research Program, National Institutes of Health	RCV003591668	SCV004819835	uncertain significance	Cardiac arrhythmia	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 789 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 14/249170 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	RCV000058498	SCV000090018	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.