PS3_Moderate, PS4, PM5, PP1, PP3

This missense variant replaces arginine with tryptophan at codon 502 in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant causes a loss of protein function with no evidence of the transcript or protein degradation and may alter kinetics of cardiac muscle contraction and relaxation (PMID: 30554920). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). This variant is known to be the most common pathogenic mutation in a diverse cohort of individuals affected with hypertrophic cardiomyopathy, occurring in 2.4% (34/1414) of the probands in one large study (PMID: 20378854). This variant has been shown to segregate with hypertrophic cardiomyopathy in over 25 families (PMID: 9562578, 20378854, 22386539). This variant has been reported in multiple unrelated affected individuals, including children with severe phenotype (PMID: 12707239, 22555271, 23054336, 23396983, 23711808, 27532257, 29121657, 35653365). This variant causes an estimated 340-fold increased risk for hypertrophic cardiomyopathy by 45 years of age, when more than 50% of carriers have overt disease (PMID: 20378854). This variant has been identified in 13/280632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg502Gln, is pathogenic (Clinvar variation ID 42540), indicating that the arginine residue at this position is important for MYBPC3 protein function. Based on the available evidence, this variant is classified as Pathogenic.

The p.R502W pathogenic mutation (also known as c.1504C>T), located in coding exon 17 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1504. The arginine at codon 502 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration, one of the most common pathogenic mutations in MYBPC3, has been reported in multiple unrelated patients with hypertrophic cardiomyopathy (HCM), and has been reported to segregate with disease in families (Richard P et al. Circulation. 2003;107(17):2227-32; Van Driest SL et al. J Am Coll Cardiol. 2004;44(9):1903-10; Saltzman AJ et al. Circ Res. 2010;106(9):1549-52; Kaski JP et al. Circ Cardiovasc Genet. 2012;5(3):317-26). Another alterations affecting this amino acid (p.R502Q, c.1505G>A) has also been reported in association with HCM (Niimura H et al. N Engl J Med. 1998;338(18):1248-57). 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 supporting evidence, this variant is interpreted as a disease-causing mutation.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 502 of the MYBPC3 protein (p.Arg502Trp). This variant is present in population databases (rs375882485, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 20378854, 22267749, 23396983). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42540). 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.Arg502 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9562578, 22386539). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Variant summary: The MYBPC3 c.1504C>T (p.Arg502Trp) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/122664 control chromosomes at a frequency of 0.0000245, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in numerous HCM patients, with evidence of co-segregation of variant with disease in some of the families. Structure study predicted the R502W mutation and other HCM-linked mutations found within the same C3 domain, may directly disrupt the interaction of cMyBP-C with other sarcomeric proteins (Zhang_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. It is the most common pathogenic HCM variant identified by our laboratory. Taken together, this variant is classified as pathogenic.

This c.1504C>T (p.Arg502Trp) variant has been reported in multiple patients with hypertrophic cardiomyopathy (HCM) [PMID 1270723, 22589294, 23396983, 20378854, 23642604]. The variant was detected in 34 individuals from a large study of 1,414 unrelated HCM patients [PMID 20378854]. From this study, it was estimated that this variant conveys a 340-fold increased risk for HCM by 45 years and the clinical prognosis worsens when this c.1504C>T (p.Arg502Trp) change occurs in the setting of a pathogenic variant in another sarcomere protein gene [PMID 20378854]. This variant is common among HCM patients, occurring in an estimated 2.4% of patients [PMID 20378854]. This variant was reported in 3 heterozygous individuals in the ExAC database (http://exac.broadinstitute.org/variant/11-47364249-G-A). Arginine at position 502 of the MYBPC3 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms predict this p.Arg502Trp change to be deleterious. This variant is thus classified as pathogenic.

The MYBPC3 c.1504C>T (p.Arg502Trp) missense variant is well documented as a pathogenic variant for hypertrophic cardiomyopathy (HCM). Across a selection of the available literature, the p.Arg502Trp variant has been identified in heterozygous state in at least 44 individuals diagnosed with HCM. Two of the individuals carried another variant in the MYBPC3 gene in a compound heterozygous state with the p.Arg502Trp variant, and another 11 carried an additional variant in either MYBPC3 or another sarcomere gene (Richard et al. 2003; Van Driest et al. 2004; Ingles et al. 2005; Maron et al. 2008; Marston et al. 2009; Saltzman et al. 2010; Kaski et al. 2012; Lopes et al. 2013; Camuglia et al. 2013). The Arg502Trp variant has also been reported in a heterozygous state in three individuals diagnosed with left ventricular noncompaction cardiomyopathy. One of the individuals was the son of a female proband with HCM who also carried the variant in a heterozygous state. The two other individuals were the brother and nephew of another proband with HCM who also carried the variant in a heterozygous state (Camuglia et al. 2013). The p.Arg502Trp variant was absent from 945 controls (Van Driest et al. 2004; Saltzman et al. 2010) and is reported at a frequency of 0.0001026 in the European (non-Finnish) population of the Genome Aggregation Database. The variant has been shown to segregate with disease in multiple families (Saltzman et al. 2010). Based on the collective evidence, the p.Arg502Trp variant is classified as pathogenic for MYBPC3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The MYBPC3 Arg502Trp s a well known cause of HCM, being reported in multiple HCM cases worldwide and segregating with HCM in families (see Ross et al. Circulation CV Genetics, 2017). The variant is present in the Exome Aggregation Consortium dataset (MAF=0.000025; http://exac.broadinstitute.org/). We have identified this variant in 14 HCM families with some segregation data (total of 7 meiosis). Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. In summary, based on segregation, extensive reports of HCM cases with the variant and rarity in the general population, we classify MYBPC3 Arg502Trp as "Pathogenic".

Published functional studies using cardiomyocytes derived from induced pluripotent stem cells demonstrate R502W alters protein function (Cohn et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18809796, 25637381, 28166811, 28615295, 22267749, 25058872, 19574547, 22589294, 20378854, 12707239, 27625337, 23711808, 27639548, 28138913, 27532257, 21310275, 27831900, 23299917, 24055113, 27000522, 28420666, 15519027, 25132132, 23396983, 23642604, 29121657, 30554920, 30316040, 31006259, 30471092, 31447099, 31980526, 33500567, 34011823, 33906374, 32686758, 33673806, 32746448, 34088380)

The p.Arg502Trp variant in MYBPC3 is a known pathogenic variant for hypertrophic cardiomyopathy (HCM). It has been reported across multiple studies in >150 individuals with HCM and has been shown to segregate with disease in multiple families (Richard 2003 PMID: 12707239, Van Driest 2004 PMID: 15519027, Carballo 2005 abstract, Ingles 2005 PMID: 16199542, Maron 2008 PMID: 18809796, Kaski 2009 PMID: 20031618, Marston 2009 PMID: 19574547, Saltzman 2010 PMID: 20378854, Walsh 2016 PMID: 27532257, LMM data, ClinVar Variation ID 42540). It has also been identified in 0.02% (11/68032) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PP1_Strong.

ACMG Criteria: PP1_S,PP5,PM1,PM2_P,PM3,PM5,PS3; Variant was found in heterozygous state

PM1_Mod PM2 PM5 PP1_Str PS4_Str

PS3, PS4, PP1_strong, PM2, PM5, PP3

This missense variant replaces arginine with tryptophan at codon 502 of the MYBPC3 protein. This variant is found within a highly conserved region of the Ig-like domain C3 (a.a. 485-502). 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. A functional study has shown that this variant causes a loss of protein function with no evidence of the transcript or protein degradation, and may alter kinetics of cardiac muscle contraction and relaxation (PMID: 30554920). This variant is known to be the most common pathogenic mutation in a diverse cohort of individuals affected with hypertrophic cardiomyopathy, occurring in 2.4% (34/1414) of affected individuals in one large study (PMID: 20378854). It has been shown that this variant segregates with disease in multiple affected individuals across more than 25 families (PMID: 9562578, 20378854, 22386539). This variant has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy, including children with severe phenotype (PMID: 12707239, 20378854, 22267749, 22555271, 23054336, 23396983, 23711808, 27532257, 29121657, 35653365, 37652022, 38186735, 38296631). This variant has been identified in 13/280632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg502Gln, is considered to be disease-causing (ClinVar variation ID: 42541), suggesting that arginine at this position is important for MYBPC3 protein function. Based on the available evidence, this variant is classified as Pathogenic.

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;For recessive disorders, detected in trans with a pathogenic variant.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP3, PM2_supporting, PS4

The MYBPC3 c.1504C>T; p.Arg502Trp variant (rs375882485) is reported in the literature in numerous individuals affected with hypertrophic cardiomyopathy and has been reported to segregate with disease in multiple families (Camuglia 2013, Kaski 2012, Lopes 2012, Maron 2008, Richard 2003, Saltzman 2010, Walsh 2014). This variant is found in the general population with an overall allele frequency of 0.005% (13/280,632 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.64). However, functional analyses suggest the variant protein has impaired interaction with sarcomeric binding partner proteins (Zhang 2014). Based on available information, this variant is considered to be pathogenic. References: Camuglia AC et al Cardiac myosin-binding protein C gene mutation expressed as hypertrophic cardiomyopathy and left ventricular noncompaction within two families: insights from cardiac magnetic resonance in clinical screening: Camuglia MYBPC3 gene mutation and MRI. Int J Cardiol. 2013 Oct 3;168(3):2950-2. PMID: 23642604. Kaski JP et al. Prevalence of sequence variants in the RAS-mitogen activated protein kinase signaling pathway in pre-adolescent children with hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2012 Jun;5(3):317-26. PMID: 22589294. Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. PMID: 23396983. Maron MS et al. Prevalence, clinical significance, and natural history of left ventricular apical aneurysms in hypertrophic cardiomyopathy. Circulation. 2008 Oct 7;118(15):1541-9. PMID: 18809796. Richard P et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003 May 6;107(17):2227-32. PMID: 12707239. Saltzman AJ et al. Short communication: the cardiac myosin binding protein C Arg502Trp mutation: a common cause of hypertrophic cardiomyopathy. Circ Res. 2010 May 14;106(9):1549-52. PMID: 20378854. 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. Zhang XL et al. Structural characterization of the C3 domain of cardiac myosin binding protein C and its hypertrophic cardiomyopathy-related R502W mutant. Biochemistry. 2014 Aug 19;53(32):5332-42. PMID: 25058872.

This is a nonsynonymous variant in the MYBPC3 gene (OMIM: 600958). Pathogenic variants in this gene have been associated with autosomal dominant hypertrophic cardiomyopathy 4. This variant has been observed to segregate with disease in at least 10 individuals from 8 families (PMID: 20378854, 23642604) (PP1_Strong). Functional studies have shown that this variant alters MYBPC3 protein function (PMID: 30554920, 25058872) (PS3). An alternate amino acid change at this position (p.Arg502Gln) has been previously reported in similarly affected individuals, which suggests that this residue is biologically important (PMID: 20433692, 22112859) (PM5). Computational algorithms produce conflicting evidence regarding the predicted functional impact of this variant (REVEL score: 0.64). This variant has a 0.0186% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant hypertrophic cardiomyopathy 4.

NM_000256.3(MYBPC3):c.1504C>T (p.Arg502Trp) is a missense variant that results in the substitution of arginine with tryptophan. The affected residue or protein region has prior evidence supporting clinical relevance. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 20378854; PMID: 22267749; PMID: 25058872; PMID: 30554920). This variant has been recurrently observed in individuals with related phenotype (PMID: 20378854; PMID: 22267749; PMID: 25058872; PMID: 30554920). Multiple computational predictions support a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic.

The c.1504C>T (p.Arg502Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This is a known Pathogenic variant that has been previously reported as a heterozygous and compound heterozygous change in patients with MYBPC3-related cardiomyopathies (PMID: 12707239, 23642604, 20378854, 25058872, 27532257, 29121657). Different amino acid changes at the same residue have been previously reported in individuals with MYBPC3-related cardiomyopathy (PMID: 9562578, 39237976, 27532257, 26090888, 37652022). Functional studies demonstrated that the c.1504C>T (p.Arg502Trp) variant results in altered protein function (PMID: 30554920). The c.1504C>T (p.Arg502Trp) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.014% (233/1613896), and is absent in the homozygous state. Based on the available evidence, c.1504C>T (p.Arg502Trp) is classified as Pathogenic.

MYBPC3: PP1:Strong, PS4, PM1, PM5, PM2:Supporting, PS3:Supporting

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 233 heterozygotes, 0 homozygotes); This variant has very strong previous evidence of pathogenicity in unrelated individuals. This is one of the most common disease causing variants observed in individuals with hypertrophic cardiomyopathy (ClinVar, PMIDs: 25634555, 32841044); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from arginine to tryptophan; This variant is heterozygous; This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM). Association to recessive disease is currently rated as limited by ClinGen; Variant is located in the annotated immunoglobulin I-set domain (DECIPHER); Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197); Variants in this gene are known to have variable expressivity (PMID: 32841044); This variant has been shown to be paternally inherited by trio analysis.

The MYBPC3 c.1504C>T variant is predicted to result in the amino acid substitution p.Arg502Trp. This variant has repeatedly been reported to segregate with disease in the heterozygous state in multiple unrelated families with hypertrophic cardiomyopathy in the literature (see for example - Richard et al. 2003. PubMed ID: 12707239; Supplementary Material, Saltzman et al. 2010. PubMed ID: 20378854). Additionally, different amino acid substitutions (p.Arg502Gly, p.Arg502Gln, p.Arg502Leu) affecting the same amino acid have been reported in individuals with hypertrophic cardiomyopathy (Human Gene Mutation Database). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and is classified as likely pathogenic or pathogenic by a majority of laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/42540/). Based on the available evidence, we interpret the MYBPC3 c.1504C>T (p.Arg502Trp) variant to be pathogenic.

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Variant interpreted as Pathogenic and reported on 07-02-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.