Submissions for variant NM_000256.3(MYBPC3):c.1468G>A (p.Gly490Arg) (rs200625851)
Total submissions: 13
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000231699 SCV000054770 uncertain significance Hypertrophic cardiomyopathy 2017-01-04 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035402 SCV000059050 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing The p.Gly490Arg variant in MYBPC3 has been reported in 14 individuals with a var iety of cardiomyopathies (8 with HCM: Van Driest 2004, Girolami 2006, Olivotto 2 008, Coppini 2014; 1 with increased left ventricular wall thickness: Morita 2006 , LMM data; 2 with DCM: Hershberger 2010, LMM data; 1 with ARVC: LMM data; and 2 individuals with LVNC: Probst 2011), and segregated with LVNC in 1 relative (Pr obst 2011). At least three of these individuals carried a second variant suffici ent to explain their disease. This variant has been reported in ClinVar (Variant ID: 42536). The p.Gly490Arg variant has also been identified in 21/66570 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs200625851). The frequency of this variant in the general popul ation raises concern as to whether it is disease causing. In summary, the clinic al significance of the p.Gly490Arg variant is uncertain.
GeneDx RCV000035402 SCV000208026 uncertain significance not specified 2017-08-01 criteria provided, single submitter clinical testing The G490R variant in the MYBPC3 gene has been reported multiple times in association with cardiomyopathy, however robust familial segregation data is lacking (Van Driest et al., 2004; Morita et al., 2006; Morita et al., 2008; Millat et al., 2010; Hershberger et al., 2010; Probst et al., 2011; Page et al., 2012; Ng et al., 2013; Bales et al., 2016). The G490R variant was not observed at any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G460R variant is classified in ClinVar as a variant of uncertain significance by multiple other clinical laboratories (SCV000059050.4, SCV000264025.1, SCV000280211.1, SCV000284213.1; Landrum et al., 2016). The G490R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G490R as a variant of uncertain significance.
Blueprint Genetics RCV000148662 SCV000264025 uncertain significance Primary familial hypertrophic cardiomyopathy 2015-03-26 criteria provided, single submitter clinical testing
Invitae RCV000231699 SCV000284213 uncertain significance Hypertrophic cardiomyopathy 2018-04-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 490 of the MYBPC3 protein (p.Gly490Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs200625851, ExAC 0.05%). This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 15519027, 16858239, 18403758, 20624503, 22267749), individuals with left ventricular non-compaction in two families (PMID: 21551322), and an individual with dilated cardiomyopathy (PMID: 20215591). However, this variant co-occurred with MYBPC3 pathogenic variants in several individuals with HCM (PMID: 1853307, 22267749, Invitae), which suggests that this c.1468G>A substitution in MYBPC3 was not the primary cause of disease in those individuals. ClinVar contains an entry for this variant (Variation ID: 42536). 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. 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.
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000054834 SCV000883088 uncertain significance Left ventricular noncompaction 10 2018-11-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770366 SCV000901807 uncertain significance Cardiomyopathy 2015-10-27 criteria provided, single submitter clinical testing
Color RCV000770366 SCV000913701 uncertain significance Cardiomyopathy 2018-09-10 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (PMID: 15519027, 16858239, 18403758, 22267749), three individuals with left ventricular non-compaction cardiomyopathy in two families (PMID: 21551322), and one individual with dilated cardiomyopathy (PMID: 22337857). However, this variant co-occurred with MYBPC3 pathogenic variants in three individuals with HCM (PMID: 22267749, 26936621), suggesting that this variant is unlikely responsible for the disease observed in these individuals. This variant has also been identified in 64/276996 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
OMIM RCV000054834 SCV000083044 pathogenic Left ventricular noncompaction 10 2011-08-01 no assertion criteria provided literature only
OMIM RCV000054800 SCV000083045 pathogenic Familial hypertrophic cardiomyopathy 4 2011-08-01 no assertion criteria provided literature only
CSER_CC_NCGL; University of Washington Medical Center RCV000148662 SCV000190386 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000035402 SCV000280211 uncertain significance not specified 2014-07-20 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.Gly490Arg In total, this variant has been reported in 14 unrelated patients with cardiomyopathy in the literature and available case data from two laboratories, in association with both HCM and DCM. However, at least 10 of these patients had other variants also identified that are considered more likely or sufficient to cause their disease (i.e. MYBPC3 frameshift variants). This variant is non-conservative, where a nonpolar glycine is exchanged for a positively charged polar arginine residue. The glycine at this residue is fully conserved across species, as are most neighboring amino acids. In silico analysis with PolyPhen predicts disease causing with a score of 0.997and mutation taster predicts disease causing. Van Driest et al. 2004 screened 389 unrelated patients with HCM for mutations in MYBPC3 at the Mayo Clinic. This cohort had been previously genotyped for mutations in MYH7, MYL2, MYL3, TNNT2, TNNI3, TPM1, and ACTC. Screened 200 controls. This Gly490Arg variant was identified in a single proband in this study and was absent from the 200 controls (100 of African American and 100 of Caucasian ancestry). No family history information or segregation data reported. Olivotto 2008: Screened 203 index patients with HCM of Italian descent. Screened patients for mutations in 8 sarcomeric genes. This variant was identified in the presence of another MYBPC3 missense variant (R502Q) in one patient. No screening for this variant in controls because it was not novel. Morita 2008: (Seidman team) Assessed 84 children with idiopathic cardiac hypertrophy on echocardiogram diagnosed before 15 years old for variants in 8 genes – MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3, MYL2, ACTC, PRKAG2, and LAMP2. Because this variant had been previously reported, they did not screen ethnicity-matched controls for this specific variant. Identified Gly490Arg in 1 child with idiopathic cardiac hypertrophy diagnosed before 15 yo. No family history or segregation information provided. Hershberger et al 2010 screened 312 patients with dilated cardiomyopathy (181 with familial DCM and 131 with idiopathic DCM) for disease-causing variants in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3. This cohort had previously been sequenced for mutations in MYH7, TNNT2, SCN5A, CSRP3, LDB3, and TCAP. The cohort was comprised of mainly individuals of Caucasian descent (290/312). All variants were absent from 246 control samples of white, Yoruban, Asian and Hispanic ancestries. Gly490Arg was identified in one proband with familial DCM, and considered "possibly disease causing" because segregation with DCM could not be assessed. Probst et al 2011 screened 63 Caucasian probands with LVNC for mutations in 8 sarcomeric genes. Screened 180 control individuals. This variant was identified in two unrelated probands with LVNC in their cohort; one patient diagnosed with LVNC @ 70 who's 32 yo affected son also carried the variant; and one patient with "sporadic" LVNC (meaning family members were not affected). This variant is present with an allele frequency of 0.035% in the European American cohort of the NHLBI Exome Sequencing project. It is currently present in ClinVar, HGMD and Harvard "ClinPath" databases as a pathogenic mutation, on the basis of the papers described above. In total, this variant has been seen in 4 of approximately 7,126 control individuals from publicly available datasets and controls in the published literature (Present in 4 of approximately 6500 individuals of African American and European American ancestry from the NHLBI ESP project; 200 controls from Van Driest et al. 2004; 246 controls from Hershberger 2010; and 180 controls from Probst et al. 2011). It is present in dbSNP (rs200625851). At this time, we do not consider this variant alone to be sufficient to explain the patient's phenotype and therefore it should not be used for risk assessment in the family. However, it is curious that this variant seems to be more prevalent in cases with cardiomyopathy vs controls, and it thus may be acting as a modifier of the phenotype in some way.