ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.2521G>C (p.Asp841His) (rs150385900)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172506 SCV000051353 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000183982 SCV000236476 likely benign not specified 2017-12-06 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000183982 SCV000269954 benign not specified 2015-10-01 criteria provided, single submitter clinical testing p.Asp841His in exon 17 of VCL: This variant is not expected to have clinical sig nificance because it has been identified in 1.3% (114/8626) of East Asian chromo somes by the Exome Aggregation Consortium (ExAC,; dbSNP rs150385900).
Ambry Genetics RCV000244937 SCV000319147 benign Cardiovascular phenotype 2016-09-10 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Illumina Clinical Services Laboratory,Illumina RCV000389914 SCV000364939 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000172506 SCV000559726 benign not provided 2019-02-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000172506 SCV000699358 benign not provided 2016-08-02 criteria provided, single submitter clinical testing Variant summary: The VCL c.2521G>C (p.Asp841His) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is not located in any known domain (InterPro, UniProt). This variant was found in 120/121210 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0132159 (114/8626). No homozygotes have been detected in general population. This frequency is about 529 times the estimated maximal expected allele frequency of a pathogenic VCL variant (0.000025), strong evidence that this is likely a benign polymorphism found primarily in the populations of East Asian origin. One of three clinical diagnostic laboratories has classified this variant as benign based on ExAC population frequency, while two other labs classify the variant as a VUS, likely due to the large ExAC database not being utalized at the time of evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and there are no published functional studies for the variant. Taken together, this variant is classified as Benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000183982 SCV000280563 uncertain significance not specified 2013-09-20 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. VCL (vinculin) is a component of Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion. It regulates cell-surface E-cadherin expression and potentiates mechanosensing by the E-cadherin complex. May also play important roles in cell morphology and locomotion. Loss of VCL mediated protein have been previously reported in association with cardiomyopathy. Maeda et al (1997) demonstrated a deficiency of cardiac metavinculin mRNA and protein in a subject with idiopathic dilated cardiomyopathy. This cytoskeletal defect was associated with abnormalities in ventricular function, cardiac dilatation, and immunohistological defects at the site of metavinculin absence: the cardiomyocyte membrane and intercalated disk. PCR of cardiac cDNA detected absence of the metavinculin transcript in cardiac tissue. PCR of genomic DNA showed that the metavinculin exon was present but not utilized in the cardiac transcript. The molecular defect appears to affect splicing of the metavinculin exon in cardiac tissue. Olson et al (2002) performed mutational analyses of the metavinculin-specific exon of VCL in 350 unrelated patients with DCM. One missense mutation (Arg975Trp) and one 3-bp deletion (Leu954del) were identified. These mutations involved conserved amino acids, were absent in 500 control individuals, and significantly altered metavinculin-mediated cross-linking of actin filaments in an in vitro assay. Vasile et al (2005) performed mutational analysis of VCL, exon 19 only on a cohort of 389 unrelated patients with clinical HCM, previously genotyped for the 8 most common HCM-associated myofilament-encoding genes. Overall, 3 nonsynonymous single nucleotide polymorphisms (A934V, P943A, and R975W) were detected in 4 patients. R975 is a highly conserved residue and R975W was absent in over 1400 reference alleles. R975W is shown in 1 individual of 6,500 people in the NHLBI database. No mouse-model data and no segregation data is available. The background probability of carrying a missense variant in VCL is approximately 1.7% (NHLBI cohort as of 4/23/13). While VCL may be a candidate gene for pre-disposition for cardiomyopathy, there is insufficient evidence at this time to suggest that any variant in VCL is sufficient enough to cause disease. This variant is novel. Asp841His results in a non-conservative amino acid substitution of a negative changed Aspartic acid with a positively charged Histidine at a position that is class conserved. In silico analysis predicts possibly damaging (Polyphen score of 0.46) and is predicted disease causing by Mutation Taster (score 81) and SIFT (0.05). This variant is not reported in dbSNP and 1000 genomes. The variant is not currently listed in NHLBI Exome Sequencng Project dataset, which included variant call on ~6,500 Caucasian and African American individuals (as of 4/22/13). Note this dataset does not match the patient's ancestry.

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