ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1786G>A (p.Gly596Arg) (rs199728019)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250820 SCV000320153 uncertain significance Cardiovascular phenotype 2017-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Blueprint Genetics, RCV000157307 SCV000207042 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-10-31 no assertion criteria provided clinical testing
Color RCV000777875 SCV000913882 uncertain significance Cardiomyopathy 2018-07-10 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the Ig-like domain C4 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact 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. This variant has been reported in individuals affected with hypertrophic cardiomyopathy in the literature (PMID 21511876, 25351510, 25558701, Ahmed et al 2012), in ClinVar (Variation ID: 42566), and on a case of sudden death (PMID 27930701). This variant is present in the general population and has been identified in 20/199106 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000656917 SCV000208048 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing The G596R variant of uncertain significance in the MYBPC3 gene has previously been reported in several unrelated individuals with HCM and one adult individual with unexplained sudden death (Chung et al., 2007; Gruner et al., 2011; Alfares et al., 2015; Lopes et al., 2015; Sanchez et al., 2017); however, detailed clinical information was often not provided. Chung et al. (2007) reported siblings with HCM who also harbored a variant in the MYH7 gene; family segregation studies were uninformative and several individuals with normal echocardiograms harbored one or both of the variants. The G596R variant has also been identified in multiple unrelated probands referred for cardiomyopathy genetic testing at GeneDx. However, many of these individuals harbored additional disease-related variants, and segregation data are currently limited due to lack of clinical information provided. The G596R variant is observed in 13/8,864 (0.15%) alleles from individuals of Ashkenazi Jewish descent in large population cohorts (Lek et al., 2016), indicating it may be a rare benign variant in this population. Nevertheless, the G596R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000204737 SCV000259413 uncertain significance Hypertrophic cardiomyopathy 2017-09-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 596 of the MYBPC3 protein (p.Gly596Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs199728019, ExAC 0.05%). This variant has been reported in an individual affected with apical hypertrophic cardiomyopathy (PMID: 21511876, 25351510). ClinVar contains an entry for this variant (Variation ID: 42566). 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 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035433 SCV000059081 uncertain significance not specified 2018-04-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000035433 SCV000280222 uncertain significance not specified 2013-01-21 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease

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