Reported variant in the literature in individuals referred for cardiomyopathy testing, but clinical and segregation data are limited or absent (Coppini et al., 2014; Ito et al., 2017; Walsh et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25524337, 28679633, 27532257, 33297573)

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1138 of the MYBPC3 protein (p.Arg1138Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25524337, 27532257, 28679633, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 42712). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The p.R1138P variant (also known as c.3413G>C), located in coding exon 31 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 3413. The arginine at codon 1138 is replaced by proline, an amino acid with dissimilar properties. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (Coppini R et al. J Am Coll Cardiol, 2014 Dec;64:2589-2600; Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Mazzarotto F et al. Genet Med, 2019 Feb;21:284-292; Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405; Micheu MM et al. Diagnostics (Basel), 2020 Dec;10; Janin A et al. Mol Diagn Ther, 2021 May;25:373-385; Field E et al. J Med Genet, 2022 Aug;59:768-775). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Variant summary: The MYBPC3 c.3413G>C (p.Arg1138Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 80556 control chromosomes and has been reported in the literature in at least one patient with HCM without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, until additional evidence becomes available, this variant is classified as VUS.

The Arg1138Pro variant in MYBPC3 has not been reported in the literature nor pre viously identified by our laboratory. The frequency of this variant in large Eur opean American and African American populations cannot be determined from the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) because coverag e at this position was insufficient or unavailable. Computational analyses (bioc hemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) sug gest that this variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. At this time, additional information is needed to fully assess the clinical significance of this variant.

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3.