ClinVar

Description

This missense variant replaces aspartic acid with valine at codon 389 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant presents in tandem on the same allele as the likely benign MYBPC3 variant c.3628-41_3628-17del25 (MYBPC3delta25bp). One functional study in wild boar tissue showed that this variant may lead to faster destabilization of sarcomere function than MYBPC3delta25bp alone (PMID: 34769381). This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. Echocardiographic findings from a study screening US South Asian individuals have indicated that left ventricular ejection fraction and left ventricular fractional shortening were significantly increased in the Asp389Val carriers compared to non-carriers, consistent with a hyperdynamic state described in early hypertrophic cardiomyopathy (PMID: 29641836). At a cellular level, cardiomyocytes derived from induced pluripotent stem cells from Asp389Val carriers were significantly more hypertrophic and showed increased frequency of arrhythmic cells as well as ectopic Ca2+ transients compared with control cells (PMID: 29641836). This variant has been identified in 1/244882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.