The p.Arg282Trp variant in MYBPC3 has been reported in 3 individuals with HCM, one of whom also carried a likely pathogenic variant in MYH7, and segregated with disease in 3 affected relatives, including 1 obligate carrier (Erdmann 2001, Erdmann 2003, Walsh 2017, LMM data). It has been identified in 0.015% (3/20520) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and reported in ClinVar (Variation ID #177621). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PP1, BP4.

Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#177621; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 12974739, 11499719, 25525159)

This missense variant replaces arginine with tryptophan at codon 282 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. An experimental functional assay has shown that this variant may cause reduced phosphorylation of the MYBPC3 protein (Giuffre et al., 2016). However, clinical significance of this observation is not known. This variant has been reported in three related individuals affected with hypertrophic cardiomyopathy (PMID: 11499719) and in an unrelated individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 5/218036 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.R282W variant (also known as c.844C>T), located in coding exon 8 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 844. The arginine at codon 282 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) (Erdmann J et al. J Am Coll Cardiol, 2001 Aug;38:322-30; Erdmann J et al. Clin Genet, 2003 Oct;64:339-49; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This missense variant replaces arginine with tryptophan at codon 282 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. In vitro experimental functional assays have shown that this variant may cause reduced phosphorylation of the MYBPC3 protein (PMID: 35227736, 38008210; DOI:10.1096/fasebj.30.1_supplement.1012.3). However, clinical significance of these observations is not known. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 12974739, 27532257). In one family, this variant segregated with disease in several affected individuals (PMID: 11499719). This variant has been identified in 5/218036 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 282 of the MYBPC3 protein (p.Arg282Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11499719, 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 177621). 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 35227736, 38008210). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.