VCL was first reported in relation to autosomal dominant hypertrophic cardiomyopathy (HCM) in 2006 (Vasile et al., PMIDs: 16236538, 16712796). Two missense variants from these initial publications have been reported in humans, but the frequency in gnomAD is above the cutoff for pathogenicity in this GCEP. Although variants in this gene have been reported in only two probands with hypertrophic cardiomyopathy, an association with dilated cardiomyopathy (DCM) has been assessed separately with a higher number or reported probands. Notably, the well-characterized p.Arg975Trp variant has been observed in both HCM and DCM cases. The mechanism for disease is believed to be gain-of-function, with mutants both failing to induce F-actin binding and promoting formation of large actin assemblies with linear bundles (PMID: 30844403). This gene-disease association is supported by expression data showing that meta-vinculin is solely expressed in the smooth and cardiac muscles (Belkin AM, et al., 1988, PMID: 3129429).
In summary, the evidence supporting the relationship between VCL and autosomal dominant hypertrophic cardiomyopathy has been disputed and no valid evidence remains to support the claim. This gene was noted to be a potential rare cause of HCM; however, no new evidence has emerged since the initial curation. More evidence is needed to either support or entirely refute the role VCL plays in this disease. This gene-disease pair was recurated by the HCM GCEP on 04/06/21 (SOP 8), and reevaluated by the Hereditary Cardiovascular Disease GCEP on 05/10/2023. As a result of this reevaluation, the classification changed from limited to disputed.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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