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 (VCL) gene illustrates these challenges. Model organism data provide 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 (odds ratio [OR] = 9.01; confidence interval [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.

中文翻译：

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评估纽蛋白功能缺失变异在遗传性心肌病中的作用。

ACMG/AMP 变体分类框架旨在用于高度渗透的孟德尔条件。尽管临床相关变异体表现出广泛的外显率，但准确评估和表达具有较低外显率的变异体的致病性可能具有挑战性。纽蛋白 ( VCL ) 基因说明了这些挑战。模式生物数据提供证据表明VCL功能丧失可能在心肌病中起作用，并且总体病例对照研究表明外显率低。 VCL然而，在受影响的先证者中很少发现功能丧失变异体，因此缺乏阐明个体变异体临床意义的家族研究。这项研究汇总了超过 18,000 名接受遗传性心肌病基因组或外显子组检测的个体的数据，确定了 32 名患有VCL功能丧失变异体的先证者，并证实了扩张型心肌病先证者的富集（优势比 [OR] = 9.01；信心区间 [CI] = 4.93–16.45)。我们的数据显示，这些人中的大多数（89.5%）患有儿科疾病。家庭研究表明， VCL杂合子功能丧失仅此一项不足以引起心肌病，但这些变异确实会增加疾病风险。总之，VCL功能丧失变异应在诊断环境中报告，但需要明确区分为具有较低的外显率。