ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.818G>A (p.Arg273His) (rs376461745)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201879 SCV000256668 uncertain significance Familial hypertrophic cardiomyopathy 1 2015-07-03 criteria provided, single submitter research This MYBPC3 Arg273His variant has been described by Olivotto I., et al (2011) in a proband with HCM and is a singleton event in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified this variant in one HCM proband who was diagnosed with HCM aged 13 years who required heart transplantation (Ingles J., et al 2005). This proband also carries an addtional pathogenic MYH7 (Arg719Gln) variant. Limited segregation data from our laboratory identified the proband's clinically affected son carried both the MYH7 and MYBPC3 variants. The proband's clinically unaffected son carries this MYBPC3 Arg273His variant only. Computational analyses (SIFT, Polyphen2, MutationTaster and CADD) are supportive of a possibly deleterious effect. More evidence and additional data is needed to confirm the role of this variant in disease. Thus, we classify this variant as of "uncertain significance".
Illumina Clinical Services Laboratory,Illumina RCV000301924 SCV000372383 uncertain significance Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000356787 SCV000372384 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000677313 SCV000372385 uncertain significance Familial hypertrophic cardiomyopathy 4 2017-04-28 criteria provided, single submitter clinical testing The MYBPC3 c.818G>A (p.Arg273His) missense variant has been reported in at least three studies in which it was found in a heterozygous state in three patients with hypertrophic cardiomyopathy (Ingles et al. 2005; Olivotto et al. 2011; Coppini et al. 2014). One of the patients also carried a heterozygous missense variant in the MYH7 gene. The MYBPC3 p.Arg273His variant was also found in a heterozygous state in an unaffected individual from the same family (Ingles et al. 2005). The p.Arg273His variant was absent from 600 control chromosomes and is reported at a frequency of 0.00012 in the South Asian population of the Exome Aggregation Consortium, but this is based on one allele only in a region of low sequence coverage. The p.Arg273 residue is conserved. The evidence for this variant is limited. The p.Arg273His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for familial hypertrophic cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000438448 SCV000513749 uncertain significance not provided 2016-12-15 criteria provided, single submitter clinical testing The R273H variant of uncertain significance in the MYBPC3 gene was first reported in a middle-agedproband with familial HCM and her affected teenage son (Ingles et al., 2005). Both proband and soneach harbored a second variant in the MYH7 gene; the proband's clinically unaffected teenage daughterwas heterozygous for only the R273H variant (Ingles et al., 2005). Subsequently, Olivotto et al.(2008) reported another individual with HCM who harbored R273H. The R273H variant was notobserved with any significant frequency in the NHLBI Exome Sequencing Project or in the ExomeAggregation Consortium (ExAC). However, R273H is a conservative amino acid substitution, which isnot likely to impact secondary protein structure as these residues share similar properties. In addition,this substitution occurs at a position that is not conserved. Nevertheless, in silico analysis predicts thisvariant is probably damaging to the protein structure/function. Finally, a missense variant at the sameresidue (R273C) has been reported in the Human Gene Mutation Database in association with HCM(Stenson et al., 2014); however, the pathogenicity of this variant has not been definitivelydetermined.Therefore, based on the currently available information, it is unclear whether this variant ispathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family memberscreening at this time.
Invitae RCV000261987 SCV000623625 uncertain significance Hypertrophic cardiomyopathy 2017-09-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 273 of the MYBPC3 protein (p.Arg273His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs376461745, ExAC 0.01%). This variant has been reported in an individual and an unrelated family affected with hypertrophic cardiomyopathy (HCM) (PMID: 16199542, 21835320). In the reported family, two affected individuals carried this variant, but they also carried a pathogenic allele in MYH7, which suggests that this c.818G>A variant was not the primary cause of disease (PMID: 16199542).This variant has also been reported in 2 individuals, 1 affected with HCM and the other with dilated cardiomyopathy (DCM) (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 161312). 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, this variant has uncertain impact on MYBPC3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
SIB Swiss Institute of Bioinformatics RCV000677313 SCV000803455 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: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2-Supporting => PM2 downgraded in strength to Supporting.
Center for Human Genetics,University of Leuven RCV000261987 SCV000886815 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770377 SCV000901818 uncertain significance Cardiomyopathy 2016-01-27 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148687 SCV000190414 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research

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