This variant (also known as Pro459fs) results in the deletion of 1 nucleotide in exon 15 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. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in seven Chinese individuals affected with hypertrophic cardiomyopathy (PMID: 21165360, 23283745, 23711808, 26090888). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.

The c.1377delC pathogenic variant, also denoted as P459fs due to alternate nomenclature, has been previously reported in six unrelated individuals with HCM, and five of these individuals were noted to be of Chinese ancestry (Lin et al., 2010; Zou et al., 2013; Liu et al., 2015; Walsh et al., 2017). It has also has been shown to segregate with HCM in one affected relative from one family (Lin et al., 2010). Additionally, c.1377delC is classified as a likely pathogenic variant in ClinVar by a different clinical laboratory in association with HCM (ClinVar SCV000219705.2 ; Landrum et al., 2016). This variant causes a shift in reading frame starting at codon leucine 460, changing it to a tryptophan, and creating a premature stop codon at position 6 of the new reading frame, denoted p.Leu460TrpfsX6. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, multiple other frameshift variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Finally, the c.1377delC variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).

The c.1377delC pathogenic mutation, located in coding exon 16 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 1377, causing a translational frameshift with a predicted alternate stop codon (p.L460Wfs*6). This variant (also referred to as Pro459fs) has been detected in several individuals reported to have hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Lin J et al. Can J Cardiol, 2010 Dec;26:518-22; Zou Y et al. Mol Biol Rep, 2013 Jun;40:3969-76; Liu X et al. Sci Rep, 2015 Jun;5:11411; Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405; Wu G et al. Circ Genom Precis Med, 2021 Oct;14:e003401; Wang Y et al. Stem Cell Res, 2021 Nov;57:102594; Liu W et al. Clin Chim Acta, 2021 Sep;520:43-52). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

This sequence change creates a premature translational stop signal (p.Leu460Trpfs*6) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21165360, 23283745, 23711808, 26090888). It has also been observed to segregate with disease in related individuals. This variant is also known as Pro459fs. ClinVar contains an entry for this variant (Variation ID: 188548). For these reasons, this variant has been classified as Pathogenic.

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.