ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.442G>A (p.Gly148Arg) (rs397516050)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Human Development Section,National Institutes of Health RCV000172015 SCV000054778 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Blueprint Genetics, RCV000172015 SCV000927487 uncertain significance not provided 2017-12-02 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000578062 SCV000744881 pathogenic Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000578062 SCV000733076 pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
GeneDx RCV000172015 SCV000208215 likely pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing The G148R (c.442 G>A) likely pathogenic variant in the MYBPC3 gene has been reported multiple times in association with cardiomyopathy (Hoedemaekers et al., 2010; Saltzman et al., 2010; Page et al., 2012; Meinke et al., 2014; Burns et al., 2017; van Velzen et al., 2017; Walsh et al., 2017). Hoedemaekers et al. (2010) reported a proband who had left ventricular non-compaction cardiomyopathy (LVNC) and was compound heterozygous for G148R and a frameshift pathogenic variant in the MYBPC3 gene. The paternally-inherited G148R was present in two affected relatives diagnosed with LVNC and HCM, respectively, and in a 49 year-old asymptomatic relative, while the frameshift variant in MYBPC3 was segregating in the maternal lineage. Saltzman et al. (2010) reported three siblings with HCM who inherited G148R from their affected father and the R502W pathogenic variant in MYBPC3 from their mother. The siblings had a more severe phenotype and earlier onset of disease as compared to their affected father. The G148R variant has been observed in multiple unrelated probands with HCM referred for genetic testing at GeneDx, and segregated with a cardiomyopathy phenotype in at least three families, in the absence of any other disease-causing variants. G148R is observed in 13/81,132 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). At the protein level, the G148R 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; yet the substitution occurs at a position that is not conserved across species. It should also be noted that several splicing algorithms predict the c.442 G>A nucleotide substitution may result in aberrant gene splicing by creating a cryptic splice site in exon 4. However, in the absence of functional mRNA studies, the consequence of the c.442 G>A nucleotide substitution cannot be precisely determined.In summary, G148R in the MYBPC3 gene is interpreted as a likely pathogenic variant.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000578062 SCV000743584 pathogenic Familial hypertrophic cardiomyopathy 4 2016-04-04 criteria provided, single submitter clinical testing
Invitae RCV000206268 SCV000259913 uncertain significance Hypertrophic cardiomyopathy 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 148 of the MYBPC3 protein (p.Gly148Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs397516050, ExAC <0.01%). This variant has been reported in the literature segregating in two families affected with hypertrophic cardiomyopathy (HCM) and/or left ventricular non compaction (LVNC) that also carried a pathogenic variant in MYBPC3 on the opposite chromosome (in trans) (PMID: 20378854, 20530761). Compound heterozygotes in these families presented a severe and early onset form of HCM and/or LVNC, while heterozygotes for any of the variants were asymptomatic or developed a milder form of HCM/LVNC. This variant has also been reported in unrelated individuals affected with HCM and/or LVNC (PMID: 22267749, 25210889, 27532257), in unaffected individuals (PMID: 23861362) and in an individual affected with arrhythmogenic right ventricular cardioyopathy (PMID: 29709087). ClinVar contains an entry for this variant (Variation ID: 42752). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035627 SCV000059278 uncertain significance not specified 2019-02-01 criteria provided, single submitter clinical testing The p.Gly148Arg variant in MYBPC3 has been reported in at least 18 individuals w ith cardiomyopathy However, 14 of the 18 probands were either compound heterozyg ous for a second pathogenic MYPBC3 variant or had additional variants in other g enes that could explain disease (Christiansen 2016, Hoedemaekers 2010, Meinke 20 14, Page 2012, van Velzen 2017, van Waning 2018, Verhagen 2018, Viswanathan 2017 , LMM data). The variant segregated with disease in 4 affected individuals from 3 families (in whom it was present without an additional HCM variant). This vari ant has also been identified in 13/83936 European chromosomes by gnomAD (http:// gnomad.broadinstitute.org). Computational prediction tools and conservation anal ysis suggest that this variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, the clinical sig nificance of the p.Gly148Arg variant is uncertain. ACMG/AMP Criteria applied: AC MG/AMP criteria applied: PS4_Supporting, PP1, PP3.
Phosphorus, Inc. RCV000578062 SCV000679776 likely pathogenic Familial hypertrophic cardiomyopathy 4 2017-08-01 criteria provided, single submitter clinical testing

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