Submissions for variant NM_000335.5(SCN5A):c.1538G>A (p.Arg513His)

gnomAD frequency: 0.00001  dbSNP: rs397517951

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041600	SCV000065296	likely benign	not specified	2012-09-28	criteria provided, single submitter	clinical testing	Arg513His in exon 12 of SCN5A: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including primates and o ther mammals. Of note, all other primates (chimp, gorilla, orangutan, and others ) have a histidine (His) at this position despite high nearby amino acid conserv ation. A disease modifying role of this variant cannot be excluded.
Invitae	RCV003654188	SCV000814974	uncertain significance	not provided	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 513 of the SCN5A protein (p.Arg513His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with sudden unexplained nocturnal death syndrome and dilated cardiomyopathy (PMID: 24529773, 27554632). ClinVar contains an entry for this variant (Variation ID: 48285). 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 histidine 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.
Color Diagnostics, LLC DBA Color Health	RCV001841589	SCV001346471	likely benign	Cardiac arrhythmia	2018-12-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298082	SCV003997035	likely benign	Cardiovascular phenotype	2023-04-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
PreventionGenetics, part of Exact Sciences	RCV003407415	SCV004106659	uncertain significance	SCN5A-related condition	2023-07-20	criteria provided, single submitter	clinical testing	The SCN5A c.1538G>A variant is predicted to result in the amino acid substitution p.Arg513His. This variant was reported in an individual with sudden unexplained nocturnal death syndrome (Liu et al 2014. PubMed ID: 24529773). This variant was also reported in an individual with cardiomyopathy (Priganc et al 2016. PubMed ID: 27554632). This variant is reported in 0.0074% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38645555-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.