ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000167911 SCV000059205 likely pathogenic Hypertrophic cardiomyopathy 2019-08-16 criteria provided, single submitter clinical testing The p.Arg1022Pro variant has been reported in >15 heterozygous individuals with HCM (Bos 2014, Brito 2005, Brito 2012, Cecconi 2016, Hazebroek 2015, Lopes 2013, Mademont-Soler 2017, Millat 2010, Walsh 2016, van Velzen 2018, Montserrat 2011- pers. comm., LMM data), 1 compound heterozygous individual with HCM (Rodriguez-Garcia 2010), and 1 compound heterozygous individual with DCM (Hazebroek 2015). This variant segregated with disease in 3 affected individuals and was absent in 2 family members with borderline LVH in one family (Rodriguez-Garcia 2010). This variant has been reported in ClinVar (Variation ID: 42682) and has been seen in 0.005% (6/127826) of European chromosomes by gnomAD ( Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP1, PP3.
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 2019-09-04 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 observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 16335287, 23396983, 28771489, 20433692); however, some individuals also carried a different pathogenic variant, suggesting that this c.3065G>C variant was not the primary cause of disease (PMID: 23782526, 20800588, 26383716). ClinVar contains an entry for this variant (Variation ID: 42682). 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. This variant disrupts the p.Arg1022 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 28790153), 22765922), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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 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
Mendelics RCV000168808 SCV001138290 uncertain significance Familial hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
Color RCV001189182 SCV001356417 uncertain significance Cardiomyopathy 2019-10-29 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001027700 SCV001190275 pathogenic Left ventricular noncompaction 10 2019-07-25 no assertion criteria provided clinical testing

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