An assessment of the role of loss of function Vinculin (VCL) variants in inherited cardiomyopathy

• Published in: Human mutation Vol. 41; no. 9; pp. 1577 - 1587
• Main Authors: Hawley, Megan H., Almontashiri, Naif, Biesecker, Leslie G., Berger, Natalie, Chung, Wendy K., Garcia, John, Grebe, Theresa A., Kelly, Melissa A., Lebo, Matthew S., Macaya, Daniela, Mei, Hui, Platt, Julia, Richard, Gabi, Ryan, Ashley, Thomson, Kate L., Vatta, Matteo, Walsh, Roddy, Ware, James S., Wheeler, Matthew, Zouk, Hana, Mason-Suares, Heather, Funke, Birgit
• Format: Journal Article
• Language: English
• Published: 24-06-2020
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.24061

The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging.
The vinculin gene (
VCL
) illustrates these challenges. Model organism data provides evidence that loss of function of
VCL
may play a role in cardiomyopathy and aggregate case-control studies suggest low penetrance.
VCL
loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants.
This study, which aggregated data from >18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with
VCL
loss-of-function variants and confirmed enrichment in probands with dilated cardiomyopathy (OR= 9.01; CI=4.93–16.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of
VCL
alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk.
In conclusion,
VCL
loss-of-function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance.