ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3065G>C (p.Arg1022Pro) (rs397516000)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000035555 SCV000208146 uncertain significance not provided 2018-05-29 criteria provided, single submitter clinical testing The R1022P variant of uncertain significance in the MYBPC3 gene has been previously reported in multiple individuals in association with HCM (Brito et al., 2005; Rodriguez-Garcia et al., 2010; Millet et al., 2010a; Millat et al., 2010b; Lopes et al., 2013; Nunez et al., 2013; Marsiglia et al., 2013; Bos et al., 2014; Cecconi et al., 2016; Walsh et al., 2016). However, in at least four cases, these individuals also harbored additional cardiogenetic variants and no segregation data was described (Millat et al. 2010a; Millat et al. 2010b; Lopes et al. 2013; Nunez et al., 2013). A single segregation study by Rodriguez-Garcia et al. (2010) identified R1022P in six individuals with HCM from two Spanish families, however, two relatives with suspected diagnoses of HCM did not harbor the R1022P variant. The R1022P variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the 1000 Genomes Project or Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The R1022P 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. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no functional or large segregation studies have been reported in order further clarify the role of this variant in disease. Additionally, although two missense variants in the same residue (R1022C, R1022S) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), their clinical significance remains to be definitively determined. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000167911 SCV000218559 likely pathogenic Hypertrophic cardiomyopathy 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 1022 of the MYBPC3 protein (p.Arg1022Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs397516000, ExAC 0.005%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 16335287, 23396983, 28771489). In addition, this variant segregated with HCM in four affected individuals. In the same family, there were two young individuals with possible HCM who did not inherit this variant (PMID: 20433692). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000167911 SCV000059205 likely pathogenic Hypertrophic cardiomyopathy 2018-01-05 criteria provided, single submitter clinical testing The p.Arg1022Pro variant has been reported in >15 individuals with HCM (Bos 2014 , Brito 2005, Brito 2012, Cecconi 2016, Hazebroek 2015, Lopes 2013, Mademont-Sol er 2017, Millat 2010, Rodriguez-Garcia 2010, Walsh 2016, Montserrat 2011- person al communication, LMM data) and 1 individual with DCM (Hazebroek 2015). One HCM proband (Nunez 2013 and the DCM proband (Hazebroek 2015) carried a second pathog enic variant sufficient to explain their disease. The p.Arg1022Pro variant segre gated with disease in 3 affected family members from one study. It was absent i n 2 family members with a "possible diagnosis" of HCM but detailed clinical data are not available (Rodriguez-Garcia 2010). This variant has been reported in Cl inVar (Variation ID: 42682) and has been seen in 6/126024 of European chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516000). Computational prediction tools and conservation analysis sug gest that the p.Arg1022Pro variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. In summary, although add itional studies are required to fully establish its clinical significance, the p .Arg1022Pro variant is likely pathogenic. ACMG/AMP Criteria applied: PS4; PP1; P P3.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000168808 SCV000256157 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000257925 SCV000747959 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-12-02 criteria provided, single submitter clinical testing

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