ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.814C>T (p.Arg272Cys) (rs397516075)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035670 SCV000059321 uncertain significance not specified 2011-06-09 criteria provided, single submitter clinical testing The Arg272Cys variant has been reported in 2 DCM probands as well as 1 possibly affected family member and was absent from at least 860 control chromosomes (Ehl ermann 209, Morales 2010, Zeller 2006). Arginine (Arg) at position 272 is conse rved across evolutionary distant species and three computer tools (AlignGVGD, Po lyphen2, SIFT) predict this change to be deleterious; however, their accuracy is unknown. While absence in controls and evolutionary conservation support a pat hogenic role, our laboratory has identified this variant in 1 Hispanic HCM proba nd (>90 Hispanic/Latino probands tested) and 1 HCM proband of mixed ethnicity. Because HCM and DCM are caused by different defects at the cellular level, it is questionable whether the same variant can cause both cardiomyopathies. This arg ues against a pathogenic role of the Arg272Cys variant when present in isolation although we cannot rule out that it may contribute to disease. In summary, add itional data is needed to determine the clinical significance of the Arg272Cys v ariant.
GeneDx RCV000766314 SCV000490636 uncertain significance not provided 2019-01-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYBPC3 gene. The R272C variant has been reported previously in association with DCM, HCM and in one case of peri-partum cardiomyopathy and was absent in greater than 800 controls (Zeller et al., 2006; Ehlermann et al., 2008; Hershberger et al., 2010; Morales et al., 2010; Millat et al., 2010; Teirlinck et al., 2012). However, informative segregation and functional data were not provided. Additionally, the R272C variant has been classified as a variant of uncertain significance by other clinical laboratories in ClinVar (SCV000059321.3, SCV000219670.1; Landrum et al., 2016). Nevertheless, the R272C variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R272C 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 where only amino acids with similar properties to Arginine are tolerated across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000688740 SCV000816363 uncertain significance Hypertrophic cardiomyopathy 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 272 of the MYBPC3 protein (p.Arg272Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs397516075, ExAC 0.02%). This variant has been reported in several individuals affected with dilated cardiomyopathy (DCM), peripartum cardiomyopathy or hypertrophic cardiomyopathy (HCM) (PMID: 16715312, 20458009, 27532257, 28771489). However, in one of the individuals with HCM, a pathogenic allele was also identified in PRKAG2, which suggests that this c.814C>T variant may not be the primary cause of disease (PMID: 28771489). ClinVar contains an entry for this variant (Variation ID: 42794). A preliminary in vitro study has suggested that this missense change decreases phosphorylation compared to the wild type (PMID: 18957093). However, the clinical significance of this data is uncertain. 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.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852436 SCV000995128 uncertain significance Long QT syndrome 2018-05-08 criteria provided, single submitter clinical testing

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