Description
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.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | not provided | not provided | not provided | not provided | | 1 | not provided | not provided | not provided |
