PS4_moderate, PM2, PP2, PP3

The p.Y1251C variant (also known as c.3752A>G), located in coding exon 33 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 3752. The tyrosine at codon 1251 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort and in two individuals from an HCM genetic testing cohort; however, clinical details were limited for these individuals (Lopes LR et al. Heart, 2015 Feb;101:294-301; myopathy patients, but clinical details are limited (Walsh R et al. Genet Med, 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This missense variant replaces tyrosine with cysteine at codon 1251 of the MYBPC3 protein. This variant is found within a highly conserved region of the Ig-like domain C10 (a.a. 1248-1266). Missense variants in this region have been shown to be significantly overrepresented in individuals with affected with hypertrophic cardiomyopathy (PMID: 30696458). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 21239446, 25351510, 27532257, 37652022). This variant has not been identified 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.

p.Tyr1251Cys (TAT>TGT): c.3752 A>G in exon 33 of the MYBPC3 gene (NM_000256.3). The Tyr1251Cys variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Tyr1251Cys results in a semi-conservative substitution of a neutral, polar Tyrosine for a polar neutral Cysteine, that could affect disulfide bonding. The Tyr1251 position is well conserved across evolution. In silico analysis predicts Tyr1251Cys is probably to the protein structure/function. Mutations in nearby residues (Gly1248Arg, Ala1255Thr) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Tyr1251Cys was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, while the Tyr1251Cys variant in the MYBPC3 gene is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant at this time. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1251 of the MYBPC3 protein (p.Tyr1251Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21239446, 25351510, 27532257, 37652022). This variant is also known as p.Tyr1250Cys. ClinVar contains an entry for this variant (Variation ID: 181021). 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. This variant disrupts the p.Tyr1251 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33782553, 34097875). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.