Submissions for variant NM_000335.5(SCN5A):c.3118G>A (p.Gly1040Arg)

gnomAD frequency: 0.00007  dbSNP: rs199473186

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000058550	SCV000637121	uncertain significance	not provided	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1040 of the SCN5A protein (p.Gly1040Arg). This variant is present in population databases (rs199473186, gnomAD 0.02%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 33641026). ClinVar contains an entry for this variant (Variation ID: 67779). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000765736	SCV000897104	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	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842329	SCV001345843	uncertain significance	Cardiac arrhythmia	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1040 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 33641026) as well as in 3 control individuals (PMID: 15851227, 19841300, 20129283). This variant has been identified in 11/280030 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	RCV002321558	SCV002607335	likely benign	Cardiovascular phenotype	2021-07-07	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.
All of Us Research Program, National Institutes of Health	RCV001842329	SCV004833188	uncertain significance	Cardiac arrhythmia	2023-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 1040 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 33641026) as well as in 3 control individuals (PMID: 15851227, 19841300, 20129283). This variant has been identified in 11/280030 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	RCV000058550	SCV000090070	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300;PMID:20129283).