ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.3163C>T (p.Arg1055Ter) (rs727505159)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766495 SCV000748347 uncertain significance not provided 2018-04-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the VCL gene. The R1055X variant has not been published as pathogenic or been reported as benign to our knowledge. The R1055X variant is not observed in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. However, no other nonsense variants in the VCL gene have been reported as definitively disease-causing variants in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). While heterozygous VCL knockout mice (VCL+/-) are viable and lack gross cardiac abnormalities, they appear to be predisposed to cardiac failure when challenged with increased hemodynamic loading, as assessed by transverse aortic constriction (Zemljic-Harpf et al., 2004). Furthermore, cardiomyocyte membrane cortical stiffness was significantly decreased in mice with cardiomyocyte-specific inactivation of one VCL allele, and normal membrane stiffness was rescued when vinculin expression was restored (Tangney et al., 2013). Nevertheless, the role of these phenomena in the development of cardiomyopathy in humans is unclear. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156630 SCV000206351 uncertain significance not specified 2017-10-23 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1055X variant in VCL has been previously identified by our laboratory in one individua l with infantile-onset DCM and one individual with possible early signs of DCM. This nonsense variant leads to a premature termination codon at position 1055, w hich is predicted to lead to a truncated or absent protein. Mouse models have sh own that loss of function of the VCL gene leads to cardiac dysfunction, includin g dilated cardiomyopathy (DCM) (Zemljic-Harpf 2007). Heterozygous loss-of-functi on variants in VCL have been identified in several individuals in our laboratory , many of whom had early onset DCM; however, these variants have also been ident ified in unaffected family members and family members with later onset disease ( LMM, unpublished data). In summary, although there is some evidence suggesting a n association between truncating variants in VCL and DCM, there is not currently enough information to determine the strength of this association or to clearly delineate a mode of inheritance. Therefore, this variant is classified as uncert ain significance. ACMG/AMP Criteria applied: PM2 (Richards 2015).

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