ClinVar

Description

Found in a 14 yo female with incomplete RBBB and two episodes of unexplained syncope during exercise. Her echocardiogram and cardiac MRI were read as normal. p.Arg1571Cys (c.4711C>T) in the MYOM1 gene (NM_003803.3), Chromosome location 18:3071885 G / A Based on the information reviewed below, we classify this as a Variant of Uncertain Significance, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. It is present, however, in population databases. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Cysteine capable of forming disulfide bridges. Arginine at this location is absolutely conserved across ~100 vertebrate species for which we have data. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant was reported in 16 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 10 out of 11,245 individuals with African ancestry (for the highest allele frequency: 0.04%), 4 Latinos (MAF 0.01%), and 2 non-Finnish Europeans. There are also 3 individuals with another change at this site: p.Arg1571His. Our patient has Latino ancestry. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.