ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.50G>A (p.Arg17Gln) (rs374630007)

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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 RCV000151174 SCV000198992 uncertain significance not specified 2013-05-01 criteria provided, single submitter clinical testing The Arg17Gln variant in MYBPC3 has not been reported in individuals with cardiom yopathy, but has been identified in 1/8408 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The affected amino acid is not well conserved in evolution, suggesting that a change may be tolerated. Other computational analyses (biochemical amino acid properties, Alig nGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impa ct to the protein. At this time, additional information is needed to fully asses s the clinical significance of this variant.
GeneDx RCV000766303 SCV000208113 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing The R17Q variant of uncertain significance in the MYBPC3 gene has previously been reported in one patient with HCM with no family history of the disease, but was also present in 1/200 healthy control individuals (Garcia-Castro et al., 2008). This variant has been identified both independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiac genetic testing at GeneDx; however, thus far, segregation data is absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. This variant is observed in 9/32876 (0.03%) alleles from individuals of Latino ancestry and in 9/105042 (0.01%) alleles from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the R17Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties.
Ambry Genetics RCV000619032 SCV000740010 uncertain significance Cardiovascular phenotype 2016-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000701754 SCV000830569 uncertain significance Hypertrophic cardiomyopathy 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 17 of the MYBPC3 protein (p.Arg17Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs374630007, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 28356264, 29121657, 25342278). ClinVar contains an entry for this variant (Variation ID: 164160). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000777988 SCV000914094 uncertain significance Cardiomyopathy 2018-10-09 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the Ig-like domain C0 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 19150014). This variant has been identified in 20/233226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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