Submissions for variant NM_000256.3(MYBPC3):c.2906-2A>G

dbSNP: rs727504333

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000154442	SCV001393297	likely pathogenic	Hypertrophic cardiomyopathy	2023-01-28	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: 177811). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 27600940). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 27 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).
GeneDx	RCV002260626	SCV002540295	pathogenic	not provided	2022-04-14	criteria provided, single submitter	clinical testing	Identified in association with hypertrophic cardiomyopathy (Alfares et al., 2015; Cecconi et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27532257, 27600940, 25611685)
Ambry Genetics	RCV002433674	SCV002750929	pathogenic	Cardiovascular phenotype	2023-02-22	criteria provided, single submitter	clinical testing	The c.2906-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides before coding exon 28 in the MYBPC3 gene. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Cecconi M et al. Int. J. Mol. Med., 2016 Oct;38:1111-24; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154442	SCV000204111	pathogenic	Hypertrophic cardiomyopathy	2013-03-04	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory