ClinVar Miner

Submissions for variant NM_014000.3(VCL):c.2924G>A (p.Arg975Gln)

gnomAD frequency: 0.00001  dbSNP: rs767325003
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000171177 SCV000221374 likely benign not specified 2016-09-28 criteria provided, single submitter research
Invitae RCV000526504 SCV000645861 uncertain significance Dilated cardiomyopathy 1W 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 975 of the VCL protein (p.Arg975Gln). This variant is present in population databases (rs767325003, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with VCL-related conditions. ClinVar contains an entry for this variant (Variation ID: 191002). 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.
Illumina Laboratory Services, Illumina RCV000526504 SCV001263887 uncertain significance Dilated cardiomyopathy 1W 2017-04-27 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.
Fulgent Genetics, Fulgent Genetics RCV002505233 SCV002816718 uncertain significance Dilated cardiomyopathy 1W; Hypertrophic cardiomyopathy 15 2021-09-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000171177 SCV004241281 likely benign not specified 2023-12-18 criteria provided, single submitter clinical testing Variant summary: VCL c.2924G>A (p.Arg975Gln) results in a conservative amino acid change in 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 3.7e-05 in 1614046 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. To our knowledge, no occurrence of c.2924G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics RCV004020044 SCV005025983 likely benign Cardiovascular phenotype 2024-01-11 criteria provided, single submitter clinical testing 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.
Breakthrough Genomics, Breakthrough Genomics RCV004692778 SCV005190855 uncertain significance not provided criteria provided, single submitter not provided

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