VCL – Hypertrophic Cardiomyopathy

Heterozygous missense variants in VCL have been reported in unrelated individuals with Hypertrophic Cardiomyopathy in the absence of known sarcomeric gene mutations. In a cohort of 228 genotype‐negative HCM patients, a novel c.829C>A (p.Leu277Met) variant was identified in one patient with severe mid‐ventricular obstruction and absent in 400 reference alleles (PMID:16712796). In a separate screen of 389 HCM probands, three additional missense changes (p.Ala934Val, p.Pro943Ala, p.Arg975Trp) were found in four patients but showed no robust pedigree segregation (PMID:16236538). No affected relatives with segregating VCL variants have been reported.

Functional studies support a pathogenic role for VCL variants in cardiac muscle remodeling. Immunohistochemistry of myectomy tissue from variant carriers reveals reduced vinculin at intercalated discs (PMID:16712796). In vitro assays and molecular modeling demonstrate that mutations in the metavinculin tail domain (e.g., p.Arg975Trp) disrupt F‐actin bundling and dimerization, leading to aberrant cytoskeletal assemblies consistent with hypertrophic remodeling (PMID:30844403). Deep‐intronic VCL variants have also been prioritized in HCM cohorts, though co‐segregation and functional validation remain limited (PMID:28797094).

Overall, the association between VCL and HCM is classified as Limited based on five unrelated probands, absence of segregation data, and supportive but non‐definitive functional evidence. Key take-home: VCL genetic testing may uncover rare risk alleles in HCM, but interpretation requires caution due to limited case numbers and lack of familial segregation.

References

• Biochemical and biophysical research communications • 2006 • A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy. PMID:16712796
• Molecular genetics and metabolism • 2006 • Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy. PMID:16236538
• Journal of molecular biology • 2019 • Cardiomyopathy Mutations in Metavinculin Disrupt Regulation of Vinculin-Induced F-Actin Assemblies. PMID:30844403
• PloS one • 2017 • Whole gene sequencing identifies deep-intronic variants with potential functional impact in patients with hypertrophic cardiomyopathy. PMID:28797094

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