Submission Details

VCL was originally curated for DCM by the ClinGen GCEP on 04/10/2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 08/09/2024. As a result, the classification did change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein.

VCL was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2011 (Wells et al, 2011, PMID: 24062880). VCL encodes a mechanosensitive protein incorporated in Z-disks, of which two splicing isoforms are produced. Metavinculin is 68 residues longer than vinculin, with exon 19 additionally spliced in, and both isoforms are expressed in the human heart.

Human genetic evidence supporting this gene-disease relationship include case-level data and case-control data. A study on 350 DCM patients sequenced on exon 19 identified 2 distinct VCL variants (one missense and one inframe deletion) in 3 patients, both absent in 500 controls. Using viscometry analysis, authors demonstrated that both variants alter actin filament organization, and confirmed this using electron microscopy. In addition, they demonstrated that the missense variant also causes disruption of the intercalated discs (Olson et al, 2002, PMID 11815424). Wells et al. (2011, PMID: 24062880) reported a missense variant segregating in a family with DCM. Given that segregation in this family was not scorable, the VCL missense variant segregating in the family was considered case-level evidence. In 2020, a large cohort-based study - comprising a primary cohort of 1040 patients and a secondary cohort of 1498 patients - highlighted a significant enrichment of predicted protein-truncating variants in the secondary cohort compared with the ExAC population database (Mazzarotto et al, 2020, PMID: 31983221). In the primary cohort, one proband was found to carry a predicted loss-of-function variant in VCL, which was scored as case-level evidence, and 10 others were found to carry 8 distinct rare missense variants. Given a general lack of substantial evidence in support of VCL missense variants’ pathogenicity, isolated missense variants in absence of any supportive evidence were not scored in this curation effort. As a result, only one variant among the aforementioned 8 was scored, as its recurrence in unrelated probands (N=3) was considered supportive of pathogenicity. A second large cohort-based study demonstrated again significant enrichment of rare, predicted protein-truncating VCL variants in 3118 DCM patients (of which 1624 overlapping those analyzed by Mazzarotto et al) compared with population individuals (Hawley et al, 2020, PMID: 32516855). Six variants carried by DCM patients not overlapping those used to score case-control enrichment in Mazzarotto et al were scored as case-level evidence, with scores adjusted based on available evidence (e.g. presence/absence of family information, presence/absence of other variants, genes screened etc). In 2023 a new study describing 5 families with DCM and rare VCL loss-of-function variants (including 3 previously described in 2022, but scored here) was published (Zahavic et al, 2023, PMID 37548861). None of the families was scorable for segregation, but all 5 were scored as case-level evidence, again with individual scores adjusted according to e.g. the presence/absence of other potentially pathogenic variants.

This gene-disease assertion is supported also by experimental evidence, comprising in vitro protein-protein interaction assays, expression studies and animal models. Direct protein-protein interaction with cardiac muscle alpha actin (encoded by ACTC1, classified as a moderate-evidence gene for DCM) and with nebulin-related anchoring protein (NRAP, strong-evidence gene for AR DCM) were demonstrated in 1981 using in vitro viscometry analysis and light and electron microscopy (Jockusch et al, 1981, PMID: 6789327), and in 1999 using ELISA (Luo et al, 1999, PMID 10320340), respectively. A study on 33 human heart specimens detected deficiency of both mRNA and protein expression in a patient with DCM (Maeda et al, 1997, PMID: 8994410). In addition, Zemljic-Harpf et al described how VCL knock-out mice showed progressive dilation of the left ventricle and a parallel decline of left-ventricular function (Zemljic-Harpf et al, 2007, PMID: 17785437).

In summary, there is strong evidence to support this gene-disease relationship. More evidence is needed to consider VCL a definitive DCM gene, as the majority of the points assigned are related to case-level evidence. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on August 9, 2024 (SOP Version 10).