Submissions for variant NM_000335.5(SCN5A):c.5269A>G (p.Ile1757Val)

dbSNP: rs1325549884

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001841937	SCV000907971	uncertain significance	Cardiac arrhythmia	2022-09-19	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1758 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 cardiovascular disorders in the literature. This variant has been identified in 1/251470 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045758	SCV001209629	uncertain significance	Brugada syndrome	2022-02-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1758 of the SCN5A protein (p.Ile1758Val). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 23158531). ClinVar contains an entry for this variant (Variation ID: 629560). 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.
Ambry Genetics	RCV002343626	SCV002641684	uncertain significance	Cardiovascular phenotype	2019-11-20	criteria provided, single submitter	clinical testing	The p.I1758V variant (also known as c.5272A>G), located in coding exon 27 of the SCN5A gene, results from an A to G substitution at nucleotide position 5272. The isoleucine at codon 1758 is replaced by valine, an amino acid with highly similar properties, and is located in the DIV-S6 transmembrane region. This variant has been detected in an individual from a long QT syndrome cohort; however, clinical details were limited (Crotti L et al. J. Am. Coll. Cardiol., 2012 Dec;60:2515-24). 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.
All of Us Research Program, National Institutes of Health	RCV001841937	SCV004815212	uncertain significance	Cardiac arrhythmia	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1758 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 cardiovascular disorders in the literature. This variant has been identified in 1/251470 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.