ClinVar Miner

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

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172015 SCV000054778 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
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 with cardiomyopathy. However, 14 of the 18 probands were either compound heterozygous for a second pathogenic MYPBC3 variant or had additional variants in other genes that could explain their disease (Christiansen 2016, Hoedemaekers 2010, Meinke 2014, 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 variant has also been identified in 0.015% (13/83936) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly148Arg variant is uncertain. ACMG/AMP Criteria applied: ACMG/AMP criteria applied: PS4_Supporting, PP1, PP3.
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.
Invitae RCV000206268 SCV000259913 uncertain significance Hypertrophic cardiomyopathy 2020-10-28 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.
Phosphorus, Inc. RCV000578062 SCV000679776 likely pathogenic Familial hypertrophic cardiomyopathy 4 2017-08-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000578062 SCV000743584 pathogenic Familial hypertrophic cardiomyopathy 4 2016-04-04 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
Blueprint Genetics RCV000172015 SCV000927487 uncertain significance not provided 2017-12-02 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845519 SCV000987622 likely pathogenic Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172015 SCV001148286 uncertain significance not provided 2016-06-01 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000206268 SCV001156274 uncertain significance Hypertrophic cardiomyopathy 2018-06-05 criteria provided, single submitter research This MYBPC3 Gly148Arg variant has previously been identified in association with HCM (Genedx, pers. comm., May 2017; LMM, pers. comm.; Meinke P, et al., 2014; Page SP, et al., 2012; Saltzman AJ, et al., 2010), Anderson Fabry disease (Page SP, et al., 2012) and LVNC (Hoedemaekers YM, et al., 2010). Two studies identified an additional variant known to be pathogenic in the families, although both families demonstrate that Gly148Arg alone may cause HCM (Saltzman AJ, et al., 2010; Hoedemaekers YM, et al., 2010). We have identified the variant in 2 HCM probands. MYBPC3 Gly148Arg has been observed resent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.0000665, which is higher than expected for disease-causing HCM variants. The variant is also present in 2 of 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts (Bick AG, et al., 2012). This missense variant is predicted to be benign by in silico tools (SIFT, PolyPhen-HCM, MutationTaster, CADD). In summary the variant has been identified in numerous HCM probands, however due to the relatively high frequency in the general population these finding may be coincidental, furthermore in silico tools predict this variant to be benign, therefore due to the conflicting evidence we classify MYBPC3 Gly148Arg as a variant of "uncertain significance".
Color Health, Inc RCV001180295 SCV001345189 uncertain significance Cardiomyopathy 2021-02-19 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 148 of the MYBPC3 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may create a new splice acceptor site, which is confirmed by a mini-gene assay (Suay-Corredera 2020). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 25210889, 27532257, 32369506) and in an exome sequencing participant not selected for arrhythmia, cardiomyopathy, or a family history of sudden death (PMID: 23861362). This variant has been reported to co-occur with a pathogenic p.Arg502Trp in the same gene in a family affected with hypertrophic cardiomyopathy and sudden cardiac death (PMID: 20378854). This variant has been reported in compound heterozygosity with a pathogenic c.2373dupG variant in an individual severely affected with left ventricular non-compaction (PMID: 20530761). Three family members carrying only this variant were either asymptomatic or developed cardiomyopathy late in life. This variant has been observed in an individual affected with sudden cardiac death and two relatives lacking hypertrophic cardiomyopathy phenotype (PMID: 31293105). This variant has also been identified in 13/200668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287162 SCV001473819 likely pathogenic none provided 2019-09-15 criteria provided, single submitter clinical testing The MYBPC3 c.442G>A; p.Gly148Arg variant (rs397516050) is reported in the literature in at least 19 unrelated individuals with cardiomyopathy, some of whom harbored additional uncertain or pathogenic variants in MYBPC3 or other genes associated with cardiomyopathy (Alfares 2010, Burns 2017, Page 2012, van Velzen 2017, van Waning 2018, Viswanathan 2017, Walsh 2017, Zimmerman 2010). This variant also segregated with disease in seven individuals from two families, including four individuals with childhood onset of cardiomyopathy who were also compound heterozygous for a second pathogenic variant in MYBPC3 (Hoedemaekers 2010, Saltzman 2010). This variant is predicted to create a cryptic splice acceptor site (Alamut v.2.11), which is supported by a functional mini-gene assay (Ito 2017); however, the physiological relevance of these observation is unknown. This variant is reported in ClinVar (Variation ID: 42752) and is found in the non-Finnish European population with an allele frequency of 0.015% (13/83,936 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered likely pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000578062 SCV000733076 pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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