ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.5851G>A (p.Val1951Met) (rs41315493)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183135 SCV000235548 likely pathogenic not provided 2013-06-09 criteria provided, single submitter clinical testing p.Val1951Met (GTG>ATG): c.5851 G>A in exon 28 of the SCN5A gene (NM_198056.2) The Val1951Met variant in the SCN5A gene has been reported in association with atrial fibrillation and Brugada syndrome (Darbar D et al., 2008; Nakajima T et al., 2011). Darbar et al. identified Val1951Met in a proband with a history of atrial fibrillation and hypertrophic cardiomyopathy, and noted it co-segregated with atrial fibrillation in four affected family members. In this family, Val1951Met did not co-segregate with an HCM phenotype. Nakajima et al. reported Val1951Met in a 25 year old Japanese patient with Brugada syndrome. Furthermore, the Val1951Met variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although mutations in nearby residues (Arg1958Gln, Ala1949Pro, Ala1949Ser) have been reported in association with arrhythmia, a different missense substitution at this residue (Val1951Leu) is classified as a polymorphism. In summary, while Val1951Met is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in LQT panel(s).
Blueprint Genetics RCV000208349 SCV000264216 uncertain significance Long QT syndrome 2 2015-08-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000249083 SCV000320476 uncertain significance Cardiovascular phenotype 2020-01-22 criteria provided, single submitter clinical testing The p.V1951M variant (also known as c.5851G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5851. The valine at codon 1951 is replaced by methionine, an amino acid with highly similar properties. This variant has been described in patients with atrial fibrillation, Brugada syndrome, and history of sudden cardiac arrest (Darbar D et al. Circulation. 2008;117(15):1927-35; Nakajima T Int Heart J. 2011;52(1):27-31; Olesen MS et al Circ Cardiovasc Genet. 2012;5(4):450-9; Song JS et al. J. Hum. Genet., 2017 Jun;62:615-620). This variant was observed to co-segregate with atrial fibrillation in one family; however, additional cardiac variants were not analyzed (Darbar D et al. Circulation. 2008;117(15):1927-35). Limited in vitro functional analysis showed some decrease in the rates of inactivation and recovery of the sodium channel, although the clinical impact of these findings has not been confirmed (Olesen MS et al Circ Cardiovasc Genet. 2012;5(4):450-9). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV001148565 SCV001309470 uncertain significance Brugada syndrome 1 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001148566 SCV001309471 uncertain significance Sick sinus syndrome 1, autosomal recessive 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001148567 SCV001309472 uncertain significance Paroxysmal familial ventricular fibrillation 1 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001150126 SCV001311139 uncertain significance Progressive familial heart block, type 1A 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001150127 SCV001311140 uncertain significance Dilated cardiomyopathy 1E 2017-04-28 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001150128 SCV001311141 likely benign Long QT syndrome 3 2017-04-28 criteria provided, single submitter clinical testing 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.
Color Health, Inc RCV001188642 SCV001355728 likely benign Arrhythmia 2018-12-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192713 SCV001361005 uncertain significance not specified 2019-11-25 criteria provided, single submitter clinical testing 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-folds 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 (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. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical and functional importance becomes available.
Invitae RCV001210931 SCV001382447 uncertain significance Brugada syndrome 2020-06-29 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1951 of the SCN5A protein (p.Val1951Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs41315493, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with SCN5A-related conditions (PMID: 21321465, 22685113, 28202948, 18378609). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68014). This variant has been reported to affect SCN5A protein 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058810 SCV000090330 not provided Atrial fibrillation no assertion provided literature only 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.

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