This variant has been previously reported as a heterozygous change in multiple individuals with hypertrophic cardiomyopathy (PMID: 15519027, 25637381, 26914223, 27532257). Functional studies in mouse cardiomyocytes have shown that this variant results in reduced protein stability (PMID: 29451820). It is absent from the gnomAD population database and thus is presumed to be rare. The c.2374T>C (p.Trp792Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2374T>C (p.Trp792Arg) variant is classified as Pathogenic.

The p.Trp792Arg variant in MYBPC3 has been previously identified in at least 19 individuals with HCM and segregated with disease in 1 affected relative (Theis 2009 PMID: 19808356, Pan 2012 PMID: 23074333, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 36605) and have been identified in 0.004% (3/67954) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). Animal models in mice have shown that this variant affects protein function (Smelter 2018 PMID: 29451820) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Trp792Arg variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PS3_Moderate.

The MYBPC3 c.2374T>C; p.Trp792Arg variant (rs187830361) is reported in the literature in numerous individuals affected with hypertrophic cardiomyopathy (Bos 2014, Murphy 2014, Pan 2012, Theis 2009, Walsh 2017, Van Driest 2004). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant is reported in ClinVar (Variation ID: 36605), and at least one study reported that this variant was overrepresented in individuals with HCM compared to general population controls (Bos 2014). The tryptophan at codon 792 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.886). Consistent with predictions, functional studies of the variant protein suggest it may lead to instability, as the variant protein occurs at lower levels in cells and exhibits an increased rate of degradation compared to wildtype MYBPC3 (Helms 2020, Smelter 2018). Based on available information, this variant is considered to be pathogenic. References: Bos JM et al. Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. Mayo Clin Proc. 2014 Jun;89(6):727-37. PMID: 24793961 Helms AS et al. Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy. Circ Genom Precis Med. 2020 Oct;13(5):396-405. PMID: 32841044 Murphy SL et al. Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy. J Cardiovasc Transl Res. 2016 Apr;9(2):153-61. PMID: 26914223 Pan S et al. Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation. Circ Cardiovasc Genet. 2012 Dec;5(6):602-10. PMID: 23074333 Smelter DF et al. The HCM-linked W792R mutation in cardiac myosin-binding protein C reduces C6 FnIII domain stability. Am J Physiol Heart Circ Physiol. 2018 Jun 1;314(6):H1179-H1191. PMID: 29451820 Theis JL et al. Expression patterns of cardiac myofilament proteins: genomic and protein analysis of surgical myectomy tissue from patients with obstructive hypertrophic cardiomyopathy. Circ Heart Fail. 2009 Jul;2(4):325-33. PMID: 19808356 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 Van Driest SL et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004 Nov 2;44(9):1903-10. PMID: 15519027

The p.W792R variant (also known as c.2374T>C), located in coding exon 24 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 2374. The tryptophan at codon 792 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals from hypertrophic cardiomyopathy cohorts (Van Driest SL et al. J. Am. Coll. Cardiol. 2004 Nov; 44: 1903-10; Theis JL et al. Circ Heart Fail 2009 Jul;2:325-33; Bos JM et al. Mayo Clin. Proc. 2014 Jun;89:727-37; Murphy SL et al. J Cardiovasc Transl Res 2016 Apr;9:153-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). One study indicated this variant may result in protein destabilization and degradation (Smelter DF. Am. J. Physiol. Heart Circ. Physiol. 2018 06;314(6):H1179-H1191). 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.

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 792 of the MYBPC3 protein (p.Trp792Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertropic cardiomyopathy (PMID: 15519027, 19808356, 23074333, 24793961, 27532257). ClinVar contains an entry for this variant (Variation ID: 36605). An algorithm developed specifically for the MYBPC3 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic.

Variant summary: MYBPC3 c.2374T>C (p.Trp792Arg) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 172418 control chromosomes. c.2374T>C has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g., van Driest_2004, Theis_2009, Pan_2012, Ho_2018). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (e.g., Smelter_2018, Helms_2020). Mouse cardiomyocytes harboring the variant protein were found to display reduced cMyBP-C protein levels and contractile kinetics similar to cells lacking endogenous cMyBP-C (Smelter_2018). The variant was also shown to contribute to protein instability (Smelter_2018, Helms_2020). Six ClinVar submitters (evaluation after 2014) have classified the variant as pathogenic (n = 3) or likely pathogenic (n = 3). Based on the evidence outlined above, the variant was classified as pathogenic.

Published functional studies demonstrate a damaging effect resulting in abnormal contractile kinetics and reduced protein stability (Smelter et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 36605); This variant is associated with the following publications: (PMID: 27114410, 34135346, 15519027, 23074333, 23299917, 24793961, 26914223, 29451820, 19808356, 25637381, 27532257, 29540445, 32841044, 31447099, 33782553)

PP3, PM2, PS3, PS4

The c.2374T>C (p.Trp792Arg) variant of the MYBPC3 gene replaces tryptophane with arginine at codon 792 of the MYBPC3 protein. This variant has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 19808356, 24793961, 25611685, 27532257). Functional studies in mouse cardiomyocytes have shown that this variant results in reduced protein expression due to destabilized C6 FnIII domain of cMyBP-C (PMID: 29451820). This variant has been identified in 7/1563840 chromosomes in the general population by the Genome Aggregation Database (gnomAD, v4.1.0). Computational prediction suggests that this variant may impact protein structure and function (REVEL score 0.886). Based on these evidence, the c.2374T>C (p.Trp792Arg) variant in the MYBPC3 gene is interpreted as likely pathogenic.