Submissions for variant NM_000256.3(MYBPC3):c.2738-2A>G

dbSNP: rs1595842632

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002948010	SCV003270422	pathogenic	Hypertrophic cardiomyopathy	2023-01-14	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 26 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23283745, 24793961, 27532257, 28615295). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003308354	SCV004001266	likely pathogenic	Cardiovascular phenotype	2023-05-08	criteria provided, single submitter	clinical testing	The c.2738-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 27 in the MYBPC3 gene. This variant has been detected in individuals from hypertrophic cardiomyopathy (HCM) cohorts (Bos JM et al. Mayo Clin Proc, 2014 Jun;89:727-37; Walsh R et al. Genet Med, 2017 Feb;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. 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 likely pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796747	SCV005416398	likely pathogenic	Hypertrophic cardiomyopathy 4		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1_Strong+PS4_Supporting+PP4
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV003308354	SCV006068386	likely pathogenic	Cardiovascular phenotype	2022-09-16	criteria provided, single submitter	clinical testing