ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3330+5G>C (rs373746463)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000247970 SCV000320055 pathogenic Cardiovascular phenotype 2017-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Good segregation with disease (lod 1.5-3 = 5-9 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Functionally-validated splicing mutation
Fulgent Genetics,Fulgent Genetics RCV000515249 SCV000611210 pathogenic Familial hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000223725 SCV000208166 pathogenic not provided 2017-07-31 criteria provided, single submitter clinical testing The c.3330+5 G>C pathogenic variant in the MYBPC3 gene has been reported to segregate with disease in one large family with HCM, and was not present in 200 control chromosomes (Watkins et al., 1995). The variant was also detected in cardiac tissue and a blood sample in an individual with HCM, and was reported in an individual with dynamic outflow tract obstruction and mild segmental hypertrophy (Nunez et al., 2013; Alhaj et al., 2013). This pathogenic variant was shown to lead to an aberrant splice transcript due to skipping of exon 30, shift in the reading frame, and premature termination of translation in exon 31 (Watkins et al., 1995). Other splice site variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Furthermore, this variant is not observed with any significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000197890 SCV000253814 pathogenic Hypertrophic cardiomyopathy 2018-12-28 criteria provided, single submitter clinical testing This sequence change affects a highly conserved nucleotide near the donor acceptor splice site of intron 30 of the MYBPC3 mRNA. This variant is present in population databases (rs373746463, ExAC 0.03%). This variant was reported to segregate with familial hypertrophic cardiomyopathy in a single family (PMID: 7493025). ClinVar contains an entry for this variant (Variation ID: 42706). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). An experimental study characterized the effect of this intronic variant and reported that this sequence change caused skipping of exon 30 and the generation of a premature stop codon which resulted in the production of an aberrant MYBPC3 protein (PMID: 7493025). In summary, this variant is a rare sequence change that has been shown to co-segregate with disease in a family affected with hypertrophic cardiomyopathy, and results in a splicing defect that causes the premature termination of the MYBPC3 protein. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000197890 SCV000059231 pathogenic Hypertrophic cardiomyopathy 2015-08-21 criteria provided, single submitter clinical testing The c.3330+5G>C variant in MYBPC3 has been reported in >12 individuals with HCM and segregated with disease in 8 affected relatives from 3 families (Watkins 199 5, Captur 2014, LMM data). It has also been reported by other clinical laborator ies in ClinVar (Variation ID 7493025) and has been identified in 7/22230 African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.or g; dbSNP rs373746463). This variant has been shown to cause skipping of exon 30, resulting in a frameshift and premature stop codon, which is predicted to lead to truncated or absent protein (Watkins 1995). Heterozygous loss of MYBPC3 funct ion is an established disease mechanism in individuals with HCM. In summary, thi s variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon presence in multiple affected individuals, very low f requency in the general population, segregation studies and the predicted impact to the protein. ACMG/AMP Criteria applied (Richards 2015): PS4_moderate, PM2, P P1_Strong, PVS1.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223725 SCV000280261 likely pathogenic not provided 2015-06-18 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 IVS30+5 G>C Based on the data reviewed below we consider this variant likely disease-causing. The variant has been reported previously in one family with HCM (Watkins H et al., 1995). Many protein-truncating variants have been reported in MYBPC3 in association with HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003), and splice variants in MYBPC3 are a well-established cause of HCM. . The variant was showed to lead to an aberrant splice transcript due to skipping of exon 30, shift in the reading frame, and premature termination of translation in exon 31. In total the variant has not been seen in ~6,600 published controls and individuals from publicly available population datasets. There is no variation at c.3330+5 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,5000 Caucasian and African American individuals (as of 9/20/13). There are only two individuals reported in this cohort with splice donor variants in MYBPC3. The variant was not observed in the following published control samples: Watkins et al, not present in 100 control individuals.

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