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

dbSNP: rs397515891

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158343	SCV000208278	pathogenic	not provided	2023-07-28	criteria provided, single submitter	clinical testing	Published RNA studies demonstrate disruption of the canoncial splice acceptor site of exon 14, resulting in a shift in reading frame and creation of a premature termination codon in exon 15 (Frank-Hansen et al., 2008); loss-of-function is a known mechanism of disease for this gene; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22267749, 27532257, 12707239, 28986452, 18337725, 29998127, 33906374)
Invitae	RCV000555457	SCV000623519	pathogenic	Hypertrophic cardiomyopathy	2022-11-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 42511). This variant is also known as IVS14–2:a10385g. Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 27532257; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 13 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547).
Revvity Omics, Revvity	RCV000158343	SCV002017648	pathogenic	not provided	2019-05-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000555457	SCV000059024	pathogenic	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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000158343	SCV001957196	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000158343	SCV001970541	pathogenic	not provided		no assertion criteria provided	clinical testing