ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.529C>T (p.Arg177Cys) (rs193922385)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619236 SCV000739993 uncertain significance Cardiovascular phenotype 2016-08-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000030291 SCV000190411 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000577978 SCV000744875 uncertain significance Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000577978 SCV000733070 uncertain significance Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
GeneDx RCV000766310 SCV000208226 uncertain significance not provided 2017-04-20 criteria provided, single submitter clinical testing The R177C variant in the MYBPC3 gene has been reported in one family with multiple individuals diagnosed with DCM and congenital heart abnormalities (Wells et al., 2011). However, the proband and other affected relatives also harbored a missense variant in the VCL gene, and the most severely affected individuals harbored both the variant in the MYBPC3 gene and in the VCL gene (Wells et al., 2011). Given that there were no relatives who harbored only the R177C variant in MYBPC3, and that one relative with DCM only harbored the familial variant in VCL, the authors concluded that the significance of the R177C variant was unclear (Wells et al., 2011). Similarly, Kindel et al. (2012) reported an individual presenting with HCM at the age of 35 with a family history of cardiomyopathy who harbored both the R177C variant and a frameshift variant in the MYBPC3 gene; however, segregation information was not available. The R177C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R177C 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. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this substitution occurs at a position that is not conserved.
Integrated Genetics/Laboratory Corporation of America RCV000151166 SCV000696332 uncertain significance not specified 2017-02-22 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.529C>T (p.Arg177Cys) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 5/5 in silico tools. This variant is located in the Ig-like C2-type 1 (InterPro), however it is unknown if it affects a critical residue in the domain. Another variant at the same residue (p.Arg177His) is present at allele frequency of 1.3% in African subpopulation of ExAC strongly suggesting it to be a likely benign polymorphism, thus the residue p.Arg177 may not be critical for protein function. The variant of interest was found in 6/95690 control chromosomes from ExAC at a frequency of 0.0000627, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). The allele frequency of this variant does exceed that of a common MYBPC3 pathogenic variant in ExAC (ie, p.Arg502Trp with allele frequency at 3/120674), arguing against pathogenicity. This variant has been found in two apparently unrelated HCM patients one of whom carried c.1235_1236delTT in other allele (Harris_2011, Kindel_2012/Internal data). Another internal sample also carried this variant along with c.1235_1236delTT. This variant has also been reported in one family with DCM and congenital heart abnormalities (Wells_2011). The proband with DCM and atrial septal defect carried this variant along with another VCL variant p.Lys815Arg (not classified by our lab, classified as VUS by a lab in ClinVar). The MYBPC3 variant was also found in 2/3 of other affected family members. Two affected relatives harboring this variant also had the VCL variant and were reported to have more severe presentation and disease course. Since one affected family member did not carry the Arg177Cys variant but the VCL variant and all three affected members did not carry the Arg177Cys variant in isolation, the authors concluded that the clinical significance of Arg177Cys is unclear. Based on the available information, this variant appears to have a phenotypic modifier only, not a causal role by itself. Multiple clinical diagnostic laboratories classified this variant as VUS, however with inclination towards possible benign outcome. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000628933 SCV000749841 uncertain significance Hypertrophic cardiomyopathy 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 177 of the MYBPC3 protein (p.Arg177Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs193922385, ExAC 0.03%). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 27532257), including a family that carried another variant of uncertain significance in the VCL gene (PMID: 24062880). This variant has also been reported in an individual with hypertrophic cardiomyopathy who carried another pathogenic variant in MYBPC3 (PMID: 22555271), which suggests that this c.529C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 36613). 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. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151166 SCV000198969 uncertain significance not specified 2018-07-16 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Arg177Cys varia nt in MYBPC3 has been reported in 1 adult with HCM who carried another pathogeni c variant in the MYBPC3 gene(Cardiogenomics) and was identified by our laborator y in 2 individuals with DCM (Wells 2011, LMM unpublished data), one of whom carr ied a second variant of unknown significance in VCL. In 1 family with DCM this v ariant was found to segregate with disease in 2/3 affected family members. The A rg177Cys variant has been identified in 1/8398 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs19 3922385). Arginine (Arg) at position 177 not well conserved in mammals or evolut ionarily distant species and the change to cysteine (Cys) was predicted to be be nign using a computational tool clinically validated by our laboratory. This too l's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In addition, another change at the same position (Arg177His) is present in 1% of the general population (42/4088 African American chromosomes, NHLBI Exome Seque ncing Project), suggesting that changes at this position may not affect the prot ein. In summary, while these data argue against a disease-causing role when pres ent in isolation, a modifying effect cannot be ruled out and additional studies are needed to fully establish the clinical significance of this variant.
Phosphorus, Inc. RCV000577949 SCV000679777 uncertain significance Left ventricular noncompaction 10 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577978 SCV000679778 uncertain significance Familial hypertrophic cardiomyopathy 4 2017-08-01 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000766310 SCV000925161 uncertain significance not provided 2017-10-24 no assertion criteria provided provider interpretation Found on postmortem testing of a 17-year-old with a negative autopsy and a history of 2 seizures in one day and then a sudden death a few months later. A 148-gene Arrhythmia and Cardiomyopathy Comprehensive Panel was done by the Invitae laboratory. This included Sudden Death in Epilepsy genes. Results included 3 variants: -p.Thr368Ile (c.1103C>T) in the DSC2 gene -p.Ala647Val (c.1940C>T) in the LAMA4 gene -p.Arg177Cys (c.529C>T) in the MYBPC3 gene p.Arg177Cys (c.529C>T) in exon 5 of the MYBPC3 gene (NM_000256.3) Chromosome location 11:47371450 G / A Based on the information reviewed below, we classify Arg177Cys as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. A different variant at this same location, Arg177His, has been classified in ClinVar as Benign by multiple labs. This variant has previously been reported in at least 3 unrelated families with cardiomyopathy, however in a family with hypertrophic cardiomyopathy there was also a pathogenic truncating variant in MYBPC3, suggesting that the Arg177Cys variant was not the primary cause of disease. LMM in ClinVar reports seeing Arg177Cys in two families with DCM; in one of these families a VUS in the VCL gene was also present. There were no affected relatives who harbored only the Arg177Cys, but there was one relative with DCM who had only the VUS in VCL, suggesting that Arg177Cys failed to segregate with disease (it was present in 3 out of 4 affected family members tested). However, the most severely affected family members each had both the MYBPC3 and VCL variants, so it is possible that they both play a role (Wells et al., 2011). This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Cysteine capable of forming disulfide bridges. Arginine at this location is poorly conserved across ~100 vertebrate species for which we have data. It is most frequently changed to another positively-charged amino acid, but Valine and Glutamine are other alternatives. There are no Likely Pathogenic or Pathogenic missense variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. LMM’s computational algorithm designed to assess the pathogenicity of variants in MYBPC3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This variant was reported in 17 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 4 East Asian ancestry individuals (for the highest allele frequency: 0.02%), 3 African, 3 Latino, and 7 non-Finnish European ancestry individuals. Overall MAF 0.0065%. Of note: Whiffin et al (2017) proposed that variants with frequency greater than 0.004% are unlikely to be pathogenic in HCM. A different variant at this same location, Arg177His, is present in 305 individuals in gnomAD, with a MAF of 1.3% among individuals with African ancestry and 0.05% among Latinos. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

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