Submissions for variant NM_000335.5(SCN5A):c.5371G>A (p.Asp1791Asn)

gnomAD frequency: 0.00003  dbSNP: rs727504495

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155630	SCV000205338	uncertain significance	not specified	2017-09-21	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000766810	SCV000235530	uncertain significance	not provided	2023-03-07	criteria provided, single submitter	clinical testing	Reported in a 10-year-old patient with bradycardia and cardiac sinus node dysfunction (Selly et al., 2012); however, this individual also harbored the A735V variant in the SCN5A gene, which has been independently associated with sudden unexplained nocturnal death syndrome and Brugada syndrome (Vatta et al., 2002; Yamagata et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28150151, 32048431, 22795782, 35650162, 36516610, 34643236)
Invitae	RCV000766810	SCV000545052	uncertain significance	not provided	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1792 of the SCN5A protein (p.Asp1792Asn). This variant is present in population databases (rs727504495, gnomAD 0.01%). This missense change has been observed in individual(s) with bradycardia (PMID: 22795782). ClinVar contains an entry for this variant (Variation ID: 178858). 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.
Color Diagnostics, LLC DBA Color Health	RCV001842486	SCV001341526	uncertain significance	Cardiac arrhythmia	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1792 of the SCN5A protein. Computational prediction suggests that this variant may have a 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 been reported in an individual affected with cardiac sinus node dysfunction (PMID: 22795782). This variant has been identified in 5/250584 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155630	SCV002104126	uncertain significance	not specified	2022-02-14	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.5374G>A (p.Asp1792Asn) results in a conservative amino acid change located in the Carboxy terminal domain (Li_2021) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250584 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5374G>A has been reported in the literature in at-least one individual affected with Cardiac sinus node dysfunction who also harbored another missense variant in SCN5A (c.2204C>T, p.Ala735Val) that has been classified as Likely Pathogenic by another clinical laboratory submitter (example, Selly_2012 and the ClinVar database). These report(s) do not provide unequivocal conclusions about association of this specific variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.