ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1505G>A (p.Arg502Gln) (rs397515907)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000168303 SCV000059055 pathogenic Hypertrophic cardiomyopathy 2017-11-28 criteria provided, single submitter clinical testing The p.Arg502Gln variant in MYBPC3 has been identified in at least 15 individuals with HCM and segregated with disease in 8 affected relatives from 3 families (N iimura 1998, Olivotto 2008, Rodriguez-Garcia 2010, Otsuka 2012, LMM data). It ha s also been reported by other clinical laboratories in ClinVar (Variation ID 425 41) and was absent from large population studies. Another missense variant in t he same codon (p.Arg502Trp) is one of the most common pathogenic MYBPC3 variants associated with HCM, supporting that this codon is critical for MYBPC3 protein function. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon presence in multiple affecte d individuals, segregation studies, absence from the general population, and occ urrence in a critical codon. ACMG/AMP criteria applied (Richards 2015): PS4, PP1 _Strong, PM5, PM2.
GeneDx RCV000158097 SCV000208032 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing The R502Q pathogenic variant in the MYBPC3 gene has been reported in the literature multiple times in association with HCM (Niimura et al., 1998; Girolami et al., 2006; Zeller et al., 2006; Miller et al., 2007; Ehlermann et al., 2008; Olivotto et al., 2008; Rudzinski et al., 2008; Rodriguez-Garcia et al., 2010; Brito et al., 2012; Otsuka et al., 2012; Page et al., 2012; Marsiglia et al., 2013; Kapplinger et al., 2014; Cecconi et al., 2016; Ripoll-Vera et al., 2016). Nimura et al. (1998) initially reported that the R502Q variant segregated with HCM in nine affected family members from two unrelated families. Otsuka et al. (2012) also reported segregation of R502Q with disease in a 45 year-old Japanese man with HCM and his affected 15 year-old son. In addition, the R502Q variant has been observed in multiple unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. The R502Q variant is not observed in large population cohorts (Lek et al., 2016). This pathogenic variant occurs in an evolutionarily conserved residue located in the C3 domain of the cardiac myosin-binding protein C. The R502Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, another missense variant at the same residue (R502W) is one of the most common pathogenic MYBPC3 variants associated with HCM and the R502 codon is considered a hot spot" for pathogenic variants (Richard et al., 2003). In summary, R502Q in the MYBPC3 gene is interpreted as a pathogenic variant."
Invitae RCV000168303 SCV000218984 pathogenic Hypertrophic cardiomyopathy 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 502 of the MYBPC3 protein (p.Arg502Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (rs397515907, ExAC no frequency). This sequence change has been reported in the literature in numerous individuals and families affected with hypertrophic cardiomyopathy (PMID: 9562578, 22386539, 16566405, 20433692, 18533079, 18403758). ClinVar contains an entry for this variant (Variation ID: 42541). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg502Trp) is reported to be deleterious (PMID: 12707239, 20378854, 22267749, 23396983). This indicates that the arginine residue is critical for MYBPC3 protein function and that other substitutions at the same position may also be deleterious. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000035407 SCV000256160 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
Ambry Genetics RCV000247256 SCV000318847 pathogenic Cardiovascular phenotype 2018-12-18 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000035407 SCV000590896 pathogenic Familial hypertrophic cardiomyopathy 4 2017-06-07 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000168303 SCV000747755 pathogenic Hypertrophic cardiomyopathy 2018-01-08 criteria provided, single submitter clinical testing This heterozygous missense variant in the MYBPC3 gene was identified in a baby with neonatal hypertrophic cardiomyopathy.
Blueprint Genetics RCV000158097 SCV000927183 pathogenic not provided 2017-02-28 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000168303 SCV000995125 pathogenic Hypertrophic cardiomyopathy 2019-06-03 criteria provided, single submitter clinical testing
Color RCV001190403 SCV001357883 pathogenic Cardiomyopathy 2019-07-20 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158097 SCV000280215 pathogenic not provided 2013-04-22 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Arg502Gln Based on the data reviewed below, we consider this variant very likely disease causing. This variant has been seen in at least 9 unrelated cases of HCM with moderately strong segregation data in two different families. Niimura et al (1998) first reported the variant in two families with HCM. The variant segregated with disease in 4 members of one family and 5 members of the other, with the furthest degree of relationship between affecteds with the variant in each family being 2nd degree. Cardim et al (2005) observed the variant in a Portugese patient with HCM. Rudzinski et al (2008) observed the variant in one Polish HCM patient. Girolami et al (2006) observed the variant in two unrelated patients with HCM (likely the same two families in Olivotto et al 2008). Morita et al (2008) observed p.Arg502Gln in a child with HCM. A German group observed the variant in one patient with HCM (Ehlermann et al 2008). This may be the same case reported in a methods paper by Zeller et al (2006). Rodriguez-Garcia et al (2010) observed the variant in two unrelated Spanish families with HCM and in one of those families there were two affected individuals with the variant. The arginine at codon 502 is highly conserved. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Another variant (p.Arg502Trp) at the same codon, which we consider very likely disease causing, was recently reported as the most common HCM-causing variant with a frequency of 2.4% in HCM patients (Saltzman et al 2010). Variants in nearby codons have also been reported in association with HCM (p.Arg495Gln, p.Lys505del, p.Gly507Arg). In total the variant has not been seen in ~418 published controls: 100 (Niimura et al 1998), 118 (Rudzinski et al 2008), 200 (Rodriguez-Garcia et al 2010). p.Arg502Gln is not listed in the NHLBI Exome Sequencing Project dataset, however, p.Arg502Trp was observed in 1 of 3472 Caucasians and 0 of 1826 Caucasians in that dataset (as of 1/16/2012). Individual phenotypes from that dataset are not available. Several different cohorts from studies on common complex cardiovascular disease were pooled to create that sample. There is no variant at codon 502 listed in dbSNP or 1000 genomes (as of 1/16/2012).
Gharavi Laboratory,Columbia University RCV000158097 SCV000809463 pathogenic not provided 2018-09-16 no assertion criteria provided research

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