ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.26-2A>G (rs376395543)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000470636 SCV000059162 pathogenic Hypertrophic cardiomyopathy 2017-04-05 criteria provided, single submitter clinical testing The c.26-2A>G variant in MYBPC3 has been reported in >10 individuals with HCM, s egregated with disease in 4 affected relatives from 3 families, including 1 obli gate carrier (Van Driest 2004, Ehlermann 2008, Waldmuller 2011, Page 2012, Kappl inger 2014, LMM unpublished data). It has also been reported in ClinVar (Variati on ID 42644), in 7/114350 of European chromosomes by the Genome Aggregation Data base (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376395543), and in 2 una ffected adults (Natarajan 2016, LMM unpublished data). For diseases with clinica l variability and reduced penetrance, pathogenic variants may be present at a lo w frequency in the general population. Finally, this variant occurs in the invar iant region (+/- 1,2) of the splice consensus sequence, and the variant is predi cted to damage the canonical splice site. Heterozygous splice variants in MYBPC3 are prevalent in cases of HCM. However, an alternate splice site is predicted t o occur 6 bps downstream, and, if used, would lead to an in-frame deletion of 2 amino acids, though these computational tools are not predictive enough to sugge st this alternative splice site would be use in vivo. In summary, this variant m eets criteria to be classified as pathogenic for HCM in an autosomal dominant ma nner based upon predicted impact to the protein, presence in affected individual s and segregation studies. ACMG/AMP Criteria applied: PS4_Moderate; PM4; PP1_Sup porting; PM2_Supporting.
GeneDx RCV000158174 SCV000208109 pathogenic not provided 2016-11-15 criteria provided, single submitter clinical testing The c.26-2 A>G pathogenic variant in the MYBPC3 gene has been reported previously in association with HCM (also reported as a>g int-1 due to alternative nomenclature) (Van Driest S et al., 2004; Ehlermann P et al., 2008). This variant destroys the canonical splice acceptor site of intron 1 and is predicted to cause abnormal gene splicing. The c.26-2 A>G variant is expected to lead to either an abnormal message, which is subjected to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the MYBPC3 gene have been reported in association with HCM. Therefore, c.26-2 A>G in the MYBPC3 gene is interpreted as a pathogenic variant.
Invitae RCV000470636 SCV000546423 pathogenic Hypertrophic cardiomyopathy 2019-10-29 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs376395543, ExAC 0.009%). This particular variant has been reported in the literature in unrelated individuals and families with hypertrophic cardiomyopathy (PMID: 15519027, 18957093, 23674513, 24510615, 22267749, 27532257). ClinVar contains an entry for this variant (Variation ID: 42644). 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 RCV000621287 SCV000739931 pathogenic Cardiovascular phenotype 2019-09-20 criteria provided, single submitter clinical testing 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;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000656561 SCV000778606 pathogenic Familial hypertrophic cardiomyopathy 4 2018-05-08 criteria provided, single submitter research
Blueprint Genetics RCV000158174 SCV000927619 pathogenic not provided 2018-04-06 criteria provided, single submitter clinical testing
Color RCV001176811 SCV001340870 likely pathogenic Cardiomyopathy 2020-03-05 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000035512 SCV000190375 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research

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