ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1928-2A>G (rs397515937)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000229899 SCV000059101 pathogenic Hypertrophic cardiomyopathy 2019-02-21 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000158133 SCV000208068 pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing The c.1928-2 A>G pathogenic variant in the MYBPC3 gene has previously been reported in multiple individuals with cardiomyopathy and has been shown to segregate with disease in at least two large families with HCM (Bonne et al., 1995; Charron et al., 1998; Erdmann et al., 2003; Fokstuen et al., 2008; Gandjbakhch et al., 2010; Teirlinck et al., 2012; Murphy et al., 2016). The c.1928-2 A>G destroys the canonical splice acceptor site of intron 20, and mRNA functional studies have demonstrated that this variant leads to aberrant gene splicing and the introduction of a premature stop codon (Bonne et al., 1995; Erdmann et al., 2001; Helms et al., 2014). Furthermore, the c.1928-2 A>G variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000229899 SCV000284218 pathogenic Hypertrophic cardiomyopathy 2018-12-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 20 of the MYBPC3 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic. This particular variant has been reported in the literature in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 7493026, 11499719, 23140321, 12707239, 18409188, 23690394, 20439259, 24510615, 20624503). ClinVar contains an entry for this variant (Variation ID: 42585). Experimental studies have shown that this missense change causes exon 21 skipping and a subsequent frameshift which leads to the introduction of a premature termination codon after residue 661 and therefore a truncated protein (PMID: 11499719, 10610770, 25031304). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000009136 SCV000299246 pathogenic Familial hypertrophic cardiomyopathy 4 2016-02-09 criteria provided, single submitter clinical testing This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to have an impact on protein function according to multiple prediction programs. In addition, the variant has been reported previously in individuals with cardiomyopathy. The c.1928-2 A>G variant affects the canonical splice acceptor site of intron 20 and leads to aberrant gene splicing and the introduction of a premature stop codon (PMID: 11499719; PMID: 7493026; PMID: 25031304).
Ambry Genetics RCV000250981 SCV000320293 pathogenic Cardiovascular phenotype 2017-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Fulgent Genetics,Fulgent Genetics RCV000515302 SCV000611208 pathogenic Familial hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2017-05-18 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000229899 SCV000886756 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000009136 SCV000897968 pathogenic Familial hypertrophic cardiomyopathy 4 2018-07-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779063 SCV000915529 pathogenic MYBPC3-Related Disorders 2018-08-14 criteria provided, single submitter clinical testing The MYBPC3 c.1928-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1928-2A>G variant has not been observed in individuals with either autosomal dominant dilated cardiomyopathy or left ventricular noncompaction cardiomyopathy. Across a selection of the available literature, the c.1928-2A>G variant has been identified in a heterozygous state in 28 families in which it was found in 82 individuals affected with hypertrophic cardiomyopathy, of whom up to 35 individuals are related, in five individuals with an unknown diagnosis or discrete signs of disease, and in six healthy carriers (Bonne et al. 1995; Charron et al. 1998; Erdmann et al. 2001; Richard et al. 2003; Teirlinck et al. 2012). The c.1928-2A>G variant was shown to segregate with disease in two four-generation French families and in a further 13 families of European origin (Bonne et al. 1995; Richard et al. 2003). One of the studies calculated disease penetrance to be 69% and described the variant as being associated with a mild ventricular hypertrophy (Charron et al. 1998). The c.1928-2A>G variant was absent from 600 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Analysis of MYBPC3 mRNA from patient lymphoblastoid cell lines showed that the c.1928-2A>G variant results in aberrant splicing, causing the skipping of exon 21 and a frameshift with the introduction of a premature stop codon after amino acid residue 661 (Bonne et al. 1995). Expression of the c.1928-2A>G variant in COS-7 cells revealed accumulation to a level similar to wild type, while in fetal rat cardiomyocytes, the variant accumulated to a level that was approximately two-thirds of wild type. Eleven percent of fetal rat cardiomyocyte cells expressing the variant localized correctly in double stripes in the A-band of the sarcomere, but in a more diffuse pattern compared to wild type (Flavigny et al. 1999). Based on the collective evidence and due to the potential impact of splice acceptor variants, the c.1928-2A>G variant is classified as pathogenic for MYBPC3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics RCV000158133 SCV000927965 pathogenic not provided 2018-09-28 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000157326 SCV000987541 pathogenic Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
OMIM RCV000009136 SCV000029353 pathogenic Familial hypertrophic cardiomyopathy 4 1995-12-01 no assertion criteria provided literature only
Blueprint Genetics RCV000157326 SCV000207061 pathogenic Primary familial hypertrophic cardiomyopathy 2014-10-07 no assertion criteria provided clinical testing

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