ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1224-2A>G (rs397515891)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158343 SCV000208278 pathogenic not provided 2016-02-29 criteria provided, single submitter clinical testing The c.1224-2 A>G mutation has been reported previously in one individual diagnosed with HCM (Page S et al., 2012). This mutation was not observed in approximately 6,000 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.1224-2 A>G mutation destroys the canonical splice acceptor site in intron 13 and is predicted to cause abnormal gene splicing. The mutation 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. Other splice site mutations in the MYBPC3 gene have been reported in association with HCM.
Invitae RCV000555457 SCV000623519 pathogenic Hypertrophic cardiomyopathy 2017-07-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 13 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 has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 27532257, Invitae). This variant is also known as IVS14–2:a10385g in the literature. ClinVar contains an entry for this variant (Variation ID: 42511). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035376 SCV000059024 pathogenic Primary familial hypertrophic cardiomyopathy 2006-10-28 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158343 SCV000280207 likely pathogenic not provided 2014-06-10 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 IVS13-2 A>G Based on the data reviewed below we consider this variant likely disease-causing. The variant has been seen in at least one unrelated case of HCM (Page et al., 2012) . Page and colleagues studied 585 consecutive, unrelated probands with HCM and noted one individual heterozygous for the above variant. Details on the phenotype of this individual were not given. In order to classify this variant as a disease-causing mutation for this paper, Page and colleagues analyzed RNA although specifics about the protein function of this particular variant was not given. No segregation data was provided. This variant was absent in 384 UK controls and 200 Danish controls. The c.1224-2 A>G variant destroys the canonical splice acceptor site in intron 13 and is predicted to cause abnormal gene splicing. The variant is predictive to lead to either an abnormal message that is subject to nonsence-mediated mRNA decay or to an abnormal protein product if the message is used for protein translation. 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. MYBPC3 splice variants reported in association with HCM include IVS2-1G>A, IVS6-2A>C IVS7+1G>A, IVS8+1G>A, IVS12-2A>G, IVS14-2A>G, IVS16-1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A). In total the variant has not been seen in ~7084 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at IVS13-2 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 7/10/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 7/10/13). The variant was not observed in the following laboratory and published control samples: Page et al., 2012 384 UK control and 200 Danish controls.

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