ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Variant summary: SCN5A c.5851G>A (p.Val1951Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.7e-05 in 246710 control chromosomes, predominantly at a frequency of 0.00067 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 27-fold over the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.5851G>A has been reported in the literature in individuals affected with Cardiomyopathy (example, Darbar_2008, Nakajima_2011, Olesen_2012, Song_2017). This included a family for which all individuals affected with atrial fibrillation (n=7) were determined to have the variant while all unaffected individuals did not; this providing evidence of the variant co-segregating with disease (Darbar_2008). A functional study, Olesen_2012, found the variant to be associated with decreased fast inactivation and positive voltage shift in recovery from inactivation. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (VUS, n=4; Likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical and functional importance becomes available.

Reported in association with atrial fibrillation, Brugada syndrome, and sudden cardiac arrest (Darbar et al., 2008; Olesen et al., 2012; Song et al., 2017; Wang et al., 2022); Identified in a proband with atrial fibrillation and hypertrophic cardiomyopathy (Nakajima et al., 2011); the variant co-segregated with atrial fibrillation in four affected family members but did not co-segregate with an HCM phenotype; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18378609, 21321465, 30203441, 32048431, 28202948, 36354768, 22685113)

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1951 of the SCN5A protein (p.Val1951Met). This variant is present in population databases (rs41315493, gnomAD 0.06%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 18378609, 21321465, 22685113, 28202948). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68014). 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 methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 22685113). 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 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.

This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609;PMID:21321465;PMID:22685113). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.