ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2672G>A (p.Arg891Gln) (rs727504378)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154535 SCV000204207 uncertain significance not specified 2014-04-09 criteria provided, single submitter clinical testing The Arg891Gln variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy and data from large population studies is insufficient to as sess its frequency in the general population. Arginine (Arg) at position 891 is highly conserved in evolution and computational prediction tools suggest that th is variant may impact the protein, though this information is not predictive eno ugh to determine pathogenicity. Another likely pathogenic variant at this positi on (Arg891Trp) has been identified in a child with HCM by our laboratory, also s upporting that a change at this position is not tolerated. Additional studies a re needed to fully assess its clinical significance.
GeneDx RCV000766359 SCV000208116 uncertain significance not provided 2018-05-11 criteria provided, single submitter clinical testing This variant is denoted p.Arg891Gln (CGG>CAG): c.2672 G>A in exon 26 of the MYBPC3 gene (NM_000256.3). The Arg891Gln variant in the MYBPC3 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Arg891Gln represents a semi-conservative amino acid substitution of a positively-charged Arginine residue with a neutral, polar Glutamine residue at a position that is highly conserved across species. In silico analysis (PolyPhen2) predicts this change to be probably damaging to the structure/function of the protein (Adzhubei I et al., 2010). The NHLBI ESP Exome Variant Server reports Arg891Gln was not observed in approximately 5000 control samples from individuals of European and African American backgrounds indicating it is unlikely to be a common benign variant in these populations. However, a polymorphism affecting a nearby residue (Val896Met) has been reported multiple times in the literature (Jaaskelainen P et al., 2002; Richard P et al., 2003; Morner S et al., 2003; Van Driest S et al., 2004), indicating this area may be tolerant of change. The Arg891Gln variant has been observed in other unrelated individuals tested for DCM.Therefore, Arg891Gln is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in DCM panel(s).
Invitae RCV000226551 SCV000284231 uncertain significance Hypertrophic cardiomyopathy 2018-06-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 891 of the MYBPC3 protein (p.Arg891Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (no rsID, ExAC 0.02%) but has not been reported in the literature. ClinVar contains an entry for this variant (Variation ID: 177884). 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. In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000244782 SCV000320180 uncertain significance Cardiovascular phenotype 2015-09-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769317 SCV000900695 uncertain significance Cardiomyopathy 2017-04-24 criteria provided, single submitter clinical testing
Color RCV000769317 SCV000914101 uncertain significance Cardiomyopathy 2018-06-11 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the fibronectin type 3 domain C7 of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 8/217904 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000766359 SCV000987353 uncertain significance not provided criteria provided, single submitter clinical testing

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