ClinVar Genomic variation as it relates to human health

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported as a novel longQT variant in 2005 - proband count not provided. Also reported in 1 ostensibly healthy adult. ClinVar: P by GeneDx

This missense variant replaces glycine with arginine at codon 579 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 long QT syndrome (PMID: 16414944). This variant has also been identified in 21/280032 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.

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 579 of the SCN5A protein (p.Gly579Arg). This variant is present in population databases (rs199473128, gnomAD 0.03%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 16414944). ClinVar contains an entry for this variant (Variation ID: 67686). 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 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.

This missense variant replaces glycine with arginine at codon 579 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 long QT syndrome (PMID: 16414944). This variant has also been identified in 21/280032 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.

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.

Variant summary: SCN5A c.1735G>A (p.Gly579Arg) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-05 in 252230 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05), strongly suggesting that the variant is benign. c.1735G>A has been reported in the literature in at-least one individual affected with Long QT Syndrome (example, Napolitano_2005) and in at-least one individual with Left ventricular noncompation (LVNC) who harbored a co-occuring likely pathogenic variant in the MYH7 gene and a pathogenic variant in the DMD gene (Alimohamed_2021) supporting possible alternative molecular basis of disease. These report(s) do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. 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 likely benign.

This variant has been reported in the following publications (PMID:20129283;PMID:16414944;PMID:19841300).