ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2905+1G>A (rs397515991)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619925 SCV000740088 pathogenic Cardiovascular phenotype 2016-11-30 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,Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Blueprint Genetics, RCV000158196 SCV000927435 pathogenic not provided 2017-10-13 criteria provided, single submitter clinical testing
GeneDx RCV000158196 SCV000208131 pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing The c.2905+1 G>A variant has been published as a pathogenic variant in at least three unrelated individuals diagnosed with HCM (Erdmann et al., 2001; Roncarati et al., 2011). In addition, this variant has been seen in multiple unrelated individuals referred for HCM genetic testing at GeneDx. Furthermore, this variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.2905+1 G>A variant destroys the canonical splice donor site in intron 27 and is predicted to cause abnormal gene splicing. Messenger RNA functional studies by Erdmann et al. (2001) demonstrated in-frame skipping of exon 27, which was hypothesized to result in loss of 56 highly conserved amino acids residues that are important for the incorporation of myosin-binding protein C into the A band. Further functional analysis by Helms et al. (2014) demonstrated in-frame skipping of exon 27 led to creation of a premature termination codon at the junction of exons 26 and 28, which resulted in mRNA instability. Finally, other splice site variants in the MYBPC3 gene have been reported in the Human Genome database in association with HCM (Stenson et al., 2014).
Invitae RCV000195678 SCV000253813 pathogenic Hypertrophic cardiomyopathy 2018-12-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 27 of the MYBPC3 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency) This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 11499719, 21959974, 21302287, 25031304). ClinVar contains an entry for this variant (Variation ID: 42666). Experimental studies which evaluated the effect of this splice site change reported in frame skipping of exon 27 and the generation of an abnormal protein product (PMID: 11499719, 25031304). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000195678 SCV000059187 pathogenic Hypertrophic cardiomyopathy 2017-07-10 criteria provided, single submitter clinical testing The c.2905+1G>A variant in MYBPC3 has been reported in >10 individuals with HCM and segregated with disease in at least 3 affected members from two families (Ki mura 1997, Erdmann 2001, Walsh 2016, LMM unpublished data) and has also been rep orted in ClinVar (Variation ID 42666). It was absent from large population studi es. This variant occurs in the invariant region (+/- 1,2) of the splice consensu s sequence and has been shown to cause altered splicing in vitro and in vivo, le ading to an abnormal or absent protein (Erdmann 2001, Helms 2014). Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, the c.2905+1G>A meets criteria to be classified as pathogenic for HC M in an autosomal dominant manner based upon presence in multiple affected indiv iduals, segregation and functional studies.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000035537 SCV000256156 uncertain significance Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158196 SCV000280252 likely pathogenic not provided 2015-06-23 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 IVS27+1 G>A Based on the data reviewed below, we consider it very likely disease causing. Many protein-truncating variants have been reported in MYBPC3 in association with HCM (Erdmann et al. 2001 & 2003; Harvard Sarcomere Protein Gene Mutation Database), and splice variants in MYBPC3 are a well-established cause of HCM. Of note, similarly-positioned donor splice site mutations in at least 7 other exons have been reported to cause HCM: IVS7+1G>A, IVS8+1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A (Harvard Sarcomere Protein Gene Mutation Database). The G at this +1 consensus splice sequence site is completely conserved across vertebrate evolution. This specific variant has been previously seen in at least 3 unrelated families. Erdmann et al. reported IVS27+1 G>A in 2001 along with weak segregation data: The variant cosegregated with disease in 2 affected members of an HCM family, an affected mother and her affected son (it was also present in an unaffected daughter). An analysis of the mRNA in HCM patients’ lymphocytes confirmed the existence of abnormal splice products; IVS27+1 G>A led to in-frame skipping of exon 27 and the loss of 56 highly conserved amino acid residues that the researchers claim are important for incorporating myosin-binding protein C into the A band. Erdmann et al. (2003) reported that the IVS27+1 G>A variant was not present in more than 50 presumably healthy controls recruited in Germany. The variant is not reported in the NHLBI Exome Sequencing Project data set (http://evs.gs.washington.edu/EVS/), nor is a +1 donor splice site variant reported for any exon of MYBPC3 as of December 28, 2011. IVS27+1 G>A is not present in dbSNP (www.ncbi.nlm.nih.gov/SNP) or 1000 Genomes (http://browser.1000genomes.org/index.html). The 1000 Genomes samples from the Bushman population appear to contain some +1 G>A variants at other exons in the MYBPC3 gene, but this was not explored in depth.

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