ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.368C>T (p.Ala123Val)

gnomAD frequency: 0.00009  dbSNP: rs765699394
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003768071 SCV000827349 uncertain significance not provided 2023-01-08 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 576224). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is present in population databases (rs765699394, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 123 of the SCN5A protein (p.Ala123Val).
Color Diagnostics, LLC DBA Color Health RCV001841867 SCV000907838 uncertain significance Cardiac arrhythmia 2023-12-02 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 123 of the SCN5A protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. This variant is found within a highly conserved N-terminus domain (a.a. 1-131). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in compound heterozygous state with SCN5A c.1379_1380del in an individual affected with congenital heart disease (PMID: 28991257). This variant has been identified in 19/249306 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 RCV001731897 SCV001983717 uncertain significance not specified 2021-09-27 criteria provided, single submitter clinical testing Variant summary: SCN5A c.368C>T (p.Ala123Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 249306 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SCN5A causing Arrhythmia (7.6e-05 vs 0.0001), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.368C>T in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two 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.
Fulgent Genetics, Fulgent Genetics RCV002477592 SCV002794070 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2021-10-14 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001841867 SCV004823277 uncertain significance Cardiac arrhythmia 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 123 of the SCN5A protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. This variant is found within a highly conserved N-terminus domain (a.a. 1-131). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in compound heterozygous state with SCN5A c.1379_1380del in an individual affected with congenital heart disease (PMID: 28991257). This variant has been identified in 19/249306 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.

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