Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 24704860, 33325730, 33087929, 37652022, 36243179, 22267749)

The p.Lys1055X variant in MYBPC3 has been identified in at least 4 individuals with HCM (Page 2012, Walsh 2017). It was absent from large population studies but has been reported in ClinVar (Variation ID #222702). This nonsense variant leads to a premature termination codon at position 1055, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.

The p.K1055* pathogenic mutation (also known as c.3163A>T), located in coding exon 29 of the MYBPC3 gene, results from an A to T substitution at nucleotide position 3163. This changes the amino acid from a lysine to a stop codon within coding exon 29. This variant has been reported in individuals from hypertrophic cardiomyopathy cohorts (Page SP et al. Circ Cardiovasc Genet, 2012 Apr;5:156-66; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM) (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 29 of 35). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other NMD predicted variants have previously been reported as pathogenic (ClinVar) (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals ~5 individuals affected with HCM (ClinVar, PMID: 22267749, 25228707) (P) 0903 - Low evidence for segregation with disease. This variant was identified in three affected individuals in one family (PMID: 22267749) (P) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 22267749, 27532257). ClinVar contains an entry for this variant (Variation ID: 222702). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys1055*) 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).