ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.1237G>A (p.Ala413Thr) (rs146278697)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000243153 SCV000318926 uncertain significance Cardiovascular phenotype 2013-09-24 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172734 SCV000051356 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000038791 SCV000236488 likely benign not specified 2018-03-02 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000543932 SCV000645834 uncertain significance Dilated cardiomyopathy 1W 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 413 of the VCL protein (p.Ala413Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs146278697, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with dilated cardiomyopathy, hypertrophic cardiomyopathy, and in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24503780, 28087426, 28771489, 28750076). ClinVar contains an entry for this variant (ClinVar ID:45575). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038791 SCV000062469 likely benign not specified 2014-12-29 criteria provided, single submitter clinical testing p.Ala413Thr in exon 10 of VCL: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 5 mammals (Guinea pig, ferret, shrew, tenrec, and Tasmanian devil) and 4 oth er evolutionary distinct species have a threonine (Thr) at this position despite high nearby amino acid conservation. This variant has been identified in 26/676 94 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs146278697).

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