ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3064C>T (p.Arg1022Cys) (rs397515999)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035553 SCV000059203 uncertain significance not specified 2016-09-27 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000766736 SCV000520819 uncertain significance not provided 2017-01-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYBPC3 gene. The R1022C variant haspreviously been reported in association with HCM (Berge et al., 2014; Bos et al., 2014; Walsh et al.,2016). This variant was notobserved at a significant frequency in approximately 6,400 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project or in the Exome AggregationConsortium (ExAC) data set, indicating it is not a common benign variant in these populations. TheR1022C variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties. Thissubstitution occurs at a position that is conserved across species, and in silico analysis predicts thisvariant is probably damaging to the protein structure/function. However, to our knowledge no studieshave been performed to determine the functional effect of the R1022C variant.
Ambry Genetics RCV000619067 SCV000740213 uncertain significance Cardiovascular phenotype 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770328 SCV000901762 uncertain significance Cardiomyopathy 2015-07-23 criteria provided, single submitter clinical testing
Invitae RCV000810358 SCV000950554 uncertain significance Hypertrophic cardiomyopathy 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1022 of the MYBPC3 protein (p.Arg1022Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs397515999, ExAC 0.01%). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 27532257, 24793961). ClinVar contains an entry for this variant (Variation ID: 42680). 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. This variant disrupts the p.Arg1022 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related disease (PMID: 19150014, 23396983, 22765922, 26383716, 22857948), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.

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