Submissions for variant NM_000256.3(MYBPC3):c.1624+2T>C

dbSNP: rs111437311

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000707508	SCV000198894	pathogenic	Hypertrophic cardiomyopathy	2017-08-31	criteria provided, single submitter	clinical testing	The c.1624+2T>C variant in MYBPC3 has been reported in 2 individuals with HCM an d segregated with disease in 3 affected relatives (variant listed as IVS17+2:t11 073c in Richard 2003, LMM data). It was absent from large population studies. Th is variant occurs in the invariant region (+/- 1,2) of the splice consensus sequ ence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splicing and other MYBPC3 variants resulting in a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets crite ria to be classified as pathogenic for HCM in an autosomal dominant manner based upon absence from controls and the predicted impact to the protein.
GeneDx	RCV000158105	SCV000208040	pathogenic	not provided	2024-04-22	criteria provided, single submitter	clinical testing	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: 19574547, 27532257, 12707239)
Ambry Genetics	RCV000617635	SCV000739929	pathogenic	Cardiovascular phenotype	2021-01-06	criteria provided, single submitter	clinical testing	The c.1624+2T>C intronic pathogenic mutation, also reported as results from a T to C substitution two nucleotides after coding exon 17 in the MYBPC3 gene. This alteration was detected in individuals reported to have hypertrophic cardiomyopathy (HCM) (Richard P et al. Circulation. 2003;107(17):2227-32 (reported as IVS17+2:t11073c); Walsh R et al. Genet Med, 2017 02;19:192-203). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000707508	SCV000836609	pathogenic	Hypertrophic cardiomyopathy	2024-10-10	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 17 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 (HCM) (PMID: 12707239, 16679492, 27532257; internal data). This variant is also known as IVS17+2t:11073c. ClinVar contains an entry for this variant (Variation ID: 164107). 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.
Daryl Scott Lab, Baylor College of Medicine	RCV002243823	SCV002515295	pathogenic	Hypertrophic cardiomyopathy 4	2022-02-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000158105	SCV003929405	pathogenic	not provided	2021-05-20	criteria provided, single submitter	clinical testing	PVS1, PM2, PS4_moderate