Submissions for variant NM_000335.5(SCN5A):c.1037A>G (p.Glu346Gly)

dbSNP: rs780735882

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413030	SCV000492087	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing	The E346G variant of uncertain significance in the SCN5A gene has not been published as a pathogenic or benign variant to our knowledge. This variant was not observed with any significant frequency in the Exome Aggregation Consortium or in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E346G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, in silico also analysis predicts E346G is probably damaging to the protein structure/function. Nevertheless, this substitution occurs at a position that is not conserved, and G346 is tolerated in at least one species.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign
Color Diagnostics, LLC DBA Color Health	RCV001841278	SCV001348695	uncertain significance	Cardiac arrhythmia	2023-09-01	criteria provided, single submitter	clinical testing	This variant is located in 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 not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 1/248886 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	RCV002392940	SCV002700803	uncertain significance	Cardiovascular phenotype	2020-12-23	criteria provided, single submitter	clinical testing	The p.E346G variant (also known as c.1037A>G), located in coding exon 8 of the SCN5A gene, results from an A to G substitution at nucleotide position 1037. The glutamic acid at codon 346 is replaced by glycine, an amino acid with similar properties, and is located in the transmembrane-spanning DI-S5/S6 region. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002506002	SCV002816607	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	2021-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524652	SCV003280952	uncertain significance	Brugada syndrome	2022-05-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 346 of the SCN5A protein (p.Glu346Gly). This variant is present in population databases (rs780735882, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 373493). 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 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.
All of Us Research Program, National Institutes of Health	RCV001841278	SCV004826692	uncertain significance	Cardiac arrhythmia	2023-10-02	criteria provided, single submitter	clinical testing	This variant is located in 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 not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 1/248886 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.