ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1961G>A (p.Arg654His) (rs1800565)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035456 SCV000059104 uncertain significance not specified 2012-10-03 criteria provided, single submitter clinical testing The Arg654His variant in MYBPC3 has been reported in 1 individual with HCM and w as absent from 200 chromosomes (Moolman-Smook 1998). It was also absent form lar ge and broad European and African American populations screened by the NHLBI Exo me Sequencing Project (rs1800565; Functional studies suggest that this variant may impact the protein, though it is not clea r whether this would result in disease (Moolman-Smook 1998, Idowu 2003). On the other hand, arginine (Arg) at position 654 is not conserved in evolution, sugges ting that a change at this position may be tolerated. The variant was also predi cted to be benign using a computational tool, which was validated by our laborat ory using a set of cardiomyopathy variants with well-established clinical signif icance. This tool's benign interpretation is estimated to be correct 89% of the time (Jordan 2011). In summary, the additional data is required to clarify the clinical significance of this variant.
Ambry Genetics RCV000251228 SCV000320588 uncertain significance Cardiovascular phenotype 2015-12-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000465385 SCV000546408 uncertain significance Hypertrophic cardiomyopathy 2017-10-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 654 of the MYBPC3 protein (p.Arg654His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in one individual affected with hypertrophic cardiomyopathy. Currently, there is not enough evidence to conclude whether this variant segregates with disease or not (PMID: 9541115). ClinVar contains an entry for this variant (Variation ID: 42588). One study on MYBPC3 protein structure has shown that this variant is important for intra-MYBPC3 interactions (PMID: 12386147). However, the clinical significance of this result is unknown. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770342 SCV000901776 uncertain significance Cardiomyopathy 2017-08-24 criteria provided, single submitter clinical testing

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