Submissions for variant NM_014000.3(VCL):c.2521G>C (p.Asp841His)

gnomAD frequency: 0.00051  dbSNP: rs150385900

Total submissions: 13

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	RCV000172506	SCV000236476	benign	not provided	2019-01-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28373245, 23861362)
Laboratory for Molecular Medicine, Mass General Brigham 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, http://exac.broadinstitute.org; dbSNP rs150385900).
Ambry Genetics	RCV000244937	SCV000319147	benign	Cardiovascular phenotype	2016-09-10	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Illumina Laboratory Services, Illumina	RCV001082235	SCV000364939	likely benign	Dilated cardiomyopathy 1W	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV001082235	SCV000559726	benign	Dilated cardiomyopathy 1W	2024-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798619	SCV002043475	benign	Cardiomyopathy	2019-09-13	criteria provided, single submitter	clinical testing
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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172506	SCV002034136	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000183982	SCV002034475	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000183982	SCV002037338	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000183982	SCV002038091	benign	not specified		no assertion criteria provided	clinical testing