Submissions for variant NM_000256.3(MYBPC3):c.1898-1G>A

dbSNP: rs730880558

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158130	SCV000208065	pathogenic	not provided	2012-08-14	criteria provided, single submitter	clinical testing	c.1898-1 G>A:IVS19-1 G>A in intron 19 of the MYBPC3 gene (NM_000256.3). Although the c.1898-1 G>A mutation in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice acceptor site in intron 19 and is predicted to cause abnormal gene splicing. This mutation is expected 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. In summary, c.1898-1 G>A in the MYBPC3 gene is interpreted as a disease-causing mutation. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044474	SCV001208273	pathogenic	Hypertrophic cardiomyopathy	2020-07-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 31112421). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23283745, 27532257, 31112421). ClinVar contains an entry for this variant (Variation ID: 180958). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 19 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158130	SCV000280228	likely pathogenic	not provided	2012-08-03	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 IVS19-1 G>A Based on the data reviewed below, we consider this variant likely disease causing. The variant is novel. This variant changes the last base of the intron for a G to an A, destroying the canonical splice acceptor site. This base is a key part of the splicing consensus sequence and is essentially always a G. Thus a change from G to A would be highly likely to affect splicing. While this specific variant has not been seen before, many protein-truncating variants have been reported in MYBPC3 in association with HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003; Harvard Sarcomere Protein Gene Mutation Database), 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 (Harvard Sarcomere Protein Gene Mutation Database). In total the variant has not been seen in ~6000 published controls and publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6000 Caucasian and African American individuals (as of 9/6/2012). In fact only one splice variant is listed in that data set and it is only present in 1/12,570 individuals. This variant is not listed in dbSNP or 1000 genomes (as of 9/6/2012).