ClinVar

Description

This variant inserts 1 nucleotide in exon 24 of the fibronectin type 3 domain C6 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. RNA studies have shown that this variant creates a new splice donor site, which could also result in a frameshift and premature truncation (PMID: 10736283). This variant has been reported in over 300 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 14563344, 19273718, 20505798, 22115648, 22574137, 35653365) and occurs in up to 25% of Dutch individuals affected with hypertrophic cardiomyopathy (PMID: 14563344, 20505798). A study of a large multigenerational family affected with hypertrophic cardiomyopathy has shown that penetrance of this variant is incomplete and age-dependent (PMID: 10736283). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 32880476), and it has also been reported in compound heterozygous or homozygous state in three Dutch neonates with lethal cardiomyopathy (PMID: 25335496). This variant has been identified in 3/172018 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.