ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.927-2A>G (rs397516082)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000531021 SCV000059333 pathogenic Hypertrophic cardiomyopathy 2019-02-01 criteria provided, single submitter clinical testing The c.927-2A>G variant in MYBPC3 has been identified in several individuals with HCM, segregated with disease in >10 affected relatives, and was absent from 400 control chromosomes (Nimura 1998, Richard 2003, Ehlermann 2008), as well as in two large and broad populations screened NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/). In addition, this variant affects the invariant (-1/-2) positions in the splice consensus sequence, and was confirmed to lead to aberrant splicing in lymphoblast cells from HCM patients with this variant (Nimura 1998). In summary, this variant meets our criteria for pathogenicity (http://pcpgm.partners.org/LMM) based on familial segregation analyses and the impact of the variant.
GeneDx RCV000158322 SCV000208257 pathogenic not provided 2018-09-04 criteria provided, single submitter clinical testing The c.927-2 A>G pathogenic variant in the MYBPC3 gene has previously been reported in multiple unrelated individuals with HCM (Niimura et al., 1998; Richard et al., 2003; Ehlermann et al., 2008; Christiaans et al., 2010; Yiu et al., 2012; Adalsteinsdottir et al., 2014; Murphy et al., 2016). This variant has been reported to segregate with disease within families, but has also been reported to have reduced penetrance (Ehlermann et al., 2008; Christiaans et al., 2010; Yiu et al., 2012). Nevertheless, this variant destroys the canonical splice acceptor site in intron 11 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. In addition, c.927-2 A>G is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Finally, other downstream splice site variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014).
Invitae RCV000531021 SCV000623630 pathogenic Hypertrophic cardiomyopathy 2019-12-11 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant is clearly defined as a hypertrophic cardiomyopathy causative allele (PMID: 25078086), and it has been reported in the literature in multiple individuals and families affected with hypertrophic cardiomyopathy (PMID: 9562578, 22574137, 27532257). ClinVar contains an entry for this variant (Variation ID: 42806). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000619499 SCV000740222 pathogenic Cardiovascular phenotype 2017-09-15 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000609977 SCV000743566 pathogenic Familial hypertrophic cardiomyopathy 4 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000609977 SCV000744860 pathogenic Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000531021 SCV000886752 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000158322 SCV000928042 pathogenic not provided 2018-11-07 criteria provided, single submitter clinical testing
Klaassen Lab,Charite University Medicine Berlin RCV000853176 SCV000995891 pathogenic Primary familial hypertrophic cardiomyopathy 2019-07-03 criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000158322 SCV001249489 pathogenic not provided 2019-08-01 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158322 SCV000280286 pathogenic not provided 2014-07-18 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 IVS11-2A>G Based on the data reviewed below, we consider this variant very likely disease causing. This variant has been seen in at least 7 unrelated published HCM cases, with strong segregation data. It was initially reported in 2 presumably unrelated French families with strong segregation data (Bonne et al 1995). All nine individuals with HCM in one family had the variant as did all 20 individuals with HCM in the other family. Christiaans et al (2010) also report at least one family with HCM and this variant (unclear if more than one or how many affected). Ehlermann et al (2008) also reported the variant in two family members with HCM. The London group included two patients with this variant in a study of cardiac phenotype in "G+LVH-" cases from their cohort (Captur et al 2014). They did not note if a family member had HCM and the variant. The variant has also likely been seen in three additional cases. The nomenclature used in these publications differs, which may be due to a difference in the exon and intron numbering scheme. Niimura et al (1998) found “Int12ASA-2G” in two families, with a total 11 individuals who were genotype and phenotype positive. Richard et al (2003) identified “IVS12–2:a7308g” in one index patient. Bonne et al (1995) sequenced mRNA from affected family members with this variant and found evidence of aberrant splicing with two mRNAs of abnormal length. One of these included a shift in frame and a resulting premature stop codon. Many other splice variants in MYBPC3 have been implicated in HCM: IVS2-1G>A, IVS6-2A>C, IVS7+1G>A, IVS8+1G>A, IVS8+5G>A, IVS12-2A>G, IVS16-1G>A, IVS15-13G>A, IVS14-2A>G, IVS18+2T>C, IVS20-2A>G, IVS21-2A>G, IVS22+2T>G, IVS22+1G>A, IVS23-2delA, IVS24+1G>A, IVS24+1G>T, IVS24-26A>G, IVS24-2A>G, IVS27+1G>A, IVS27+1delGT, IVS27-3C>G, IVS28+1G>A, IVS32+1G>A, IVS33+1G>A (see http://cardiogenomics.med.harvard.edu/project-detail?project_id=230 for list and references). In total the variant has not been seen in 6800 laboratory controls, published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of August 25th, 2014). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of August 25th,2014). The variant was not observed in the following laboratory and published control samples: 200 laboratory controls (GeneDx), 100 published controls (Boone et al 1995).
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000609977 SCV000733058 pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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