ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2197C>T (p.Arg733Cys) (rs397515956)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035475 SCV000059123 uncertain significance not specified 2017-08-29 criteria provided, single submitter clinical testing The p.Arg733Cys variant in MYBPC3 has been reported in at least 2 individuals wi th HCM (Van Driest 2004, LMM data). This variant has been identified in 9/126440 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org/; dbSNP rs397515956). This variant has been reported in Cl inVar (Variant ID: 42607). Arginine (Arg) at position 733 is not conserved in m ammals, or evolutionarily distant species and the change to cystine (Cys) was pr edicted to be benign using a computational tool clinically validated by our labo ratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In addition, this amino acid change is present in the rhesus mac aque. In summary, the clinical significance of the p.Arg733Cys variant is uncer tain.
GeneDx RCV000766347 SCV000208078 uncertain significance not provided 2014-12-01 criteria provided, single submitter clinical testing p.Arg733Cys (CGC>TGC): c.2197 C>T in exon 23 of the MYBPC3 gene (NM_000256.3) The R733C variant in the MYBPC3 gene has been previously reported in association with HCM and was not identified in 400 healthy control alleles (Van Driest S et al., 2004). Nevertheless, no specific disease phenotype or segregation studies were reported. The R733C variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This 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 in mammals. A nearby missense mutation (R726C) has been reported in association with HCM. However, in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with HCM, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (DCM) (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Invitae RCV000227952 SCV000284223 uncertain significance Hypertrophic cardiomyopathy 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 733 of the MYBPC3 protein (p.Arg733Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs397515956, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 27532257) but also in 1/427 healthy control individuals (PMID: 24510615). Currently there is insufficient evidence to conclude whether this variant segregates with disease or not. ClinVar contains an entry for this variant (Variation ID: 42607). 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.
Fulgent Genetics,Fulgent Genetics RCV000515397 SCV000611409 uncertain significance Familial hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2017-05-23 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000677325 SCV000803547 uncertain significance Familial hypertrophic cardiomyopathy 4 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Cardiomyopathy, familial hypertrophic, 4, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2-Supporting =>PM2 downgraded in strength to Supporting.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000227952 SCV000996343 uncertain significance Hypertrophic cardiomyopathy 2017-03-22 criteria provided, single submitter research This MYBPC3 Arg733Cys variant has been reported in 1 HCM proband by Van Driest et al. (2004) in their cohort of 389 unrelated HCM probands, where only the MYBPC3 gene was screened and 2 HCM probands by Walsh et al. (2017). The variant has also been identified in 1 control (Kapplinger JD, et al., 2014) and is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at an allele frequency >0.00008, which is higher then expected for HCM. We have identified this variant in 1 HCM proband who experienced a resuscitated cardiac arrest. This proband also carries an additional known pathogenic splice variant in MYBPC3 (c.1928-2A>G). Computational analyses (SIFT, MutationTaster) support a potentially deleterious effect. However, a tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts this variant to have a "benign" affect. Based on the elevated allele frequency in the general population, observation of the variant in 1 control and a total of 4 HCM probands, we classify MYBPC3 Arg733Cys as variant of "uncertain significance".
Mendelics RCV000677325 SCV001138299 uncertain significance Familial hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000035475 SCV000280232 uncertain significance not specified 2015-02-25 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.Arg733Cys Given weak case data and the fact that few pathogenic variants in MYBPC3 are missense, we consider it a variant of uncertain significance. The variant has been seen in at least one case of HCM (not including this patient's family). There is no segregation data available. Dr. Ackerman's group reported the variant in one patient with HCM from their 389 patient Mayo cohort (van Driest et al 2004). No ancestry or segregation data was reported. They only analyzed MYBPC3 in that study. The arginine at codon 733 is only partially conserved across species, with a histidine at that position in some non-mammals. This is a non-conservative amino acid substitution (Grantham score 180). I could find only one nearby missense variant (p.Arg726Cys (HGMD, Seidmans' database)). Of note, the majority of disease-causing variants in MYBPC3 are splice, nonsense, or frameshift variants. The splicing algorithms that mutationtaster uses did not predict a significant effect on splicing.

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