ClinVar Genomic variation as it relates to human health

The MYBPC3 c.709T>C variant is predicted to result in the amino acid substitution p.Tyr237His. This variant has been reported in an individual with hypertrophic cardiomyopathy (Waldmuller et al. 2008. PubMed ID: 18258667) and an individual with left ventricular noncompaction (Table S1, Schultze-Berndt et al. 2021. PubMed ID: 34540771). Additionally, different missense variants affecting this amino acid (p.Tyr237Ser, p.Tyr237Cys) have been reported in individuals with hypertrophic cardiomyopathy (Table S1A/B – Walsh et al. 2017. PubMed ID: 27532257; García-Castro et al. 2009. PubMed ID: 19150014). Functional studies of the p.Tyr237Ser variant found it accelerates contractile function (Doh et al. 2019. PubMed ID: 30611859). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.

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. This variant disrupts the p.Tyr237 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12818575, 24111713, 27532257, 30611859). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 181047). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or left ventricular noncompaction cardiomyopathy (PMID: 18258667, 34540771; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 237 of the MYBPC3 protein (p.Tyr237His).

The p.Y237H variant (also known as c.709T>C), located in coding exon 6 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 709. The tyrosine at codon 237 is replaced by histidine, an amino acid with similar properties. This alteration has been detected in several individuals with hypertrophic cardiomyopathy (Waldmüller S et al. Clin. Chem. 2008;54:682-7; Wang J et al. Eur J Heart Fail, 2014 Sep;16:950-7; Ambry internal data; external communication). This alteration has also been reported in a left ventricular non-compaction cohort (Schultze-Berndt A et al. Front Pediatr, 2021 Sep;9:722926). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID 181047; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28679633, 18258667)

The MYBPC3 c.709T>C; p.Tyr237His variant (rs730880624) is reported in the literature in individuals affected with hypertrophic cardiomyopathy (HCM) or left ventricular noncompaction (Schultze-Berndt 2021, Waldmuller 2008, Wang 2008). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.919). Additionally, other variants at this codon (c.710A>G; p.Tyr237Ser, c.710A>G; p.Tyr237Cys) have been reported in individuals with HCM (Coto 2012, Garcia-Castro 2009, Morner 2003, Walsh 2017). Based on available information, the p.Tyr237His variant is considered to be likely pathogenic. References: Coto E et al. Resequencing the whole MYH7 gene (including the intronic, promoter, and 3' UTR sequences) in hypertrophic cardiomyopathy. J Mol Diagn. 2012 Sep;14(5):518-24. PMID: 22765922. Garcia-Castro M et al. Espectro mutacional de los genes sarcoméricos MYH7, MYBPC3, TNNT2, TNNI3 y TPM1 en pacientes con miocardiopatía hipertrófica [Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. Rev Esp Cardiol. 2009 Jan;62(1):48-56. Spanish. PMID: 19150014. Morner S et al. Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden. J Mol Cell Cardiol. 2003 Jul;35(7):841-9. PMID: 12818575. Schultze-Berndt A et al. Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy. Front Pediatr. 2021 Sep 3;9:722926. PMID: 34540771. Waldmuller S et al. Array-based resequencing assay for mutations causing hypertrophic cardiomyopathy. Clin Chem. 2008 Apr;54(4):682-7. PMID: 18258667. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257. Wang J et al. Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy. Eur J Heart Fail. 2014 Sep;16(9):950-7. PMID: 25132132.