Submissions for variant NM_000256.3(MYBPC3):c.1624+2T>C (rs111437311)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617635	SCV000739929	pathogenic	Cardiovascular phenotype	2017-02-27	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx	RCV000158105	SCV000208040	pathogenic	not provided	2016-10-18	criteria provided, single submitter	clinical testing	c.1624+2 T>C: IVS17+2 T>C in intron 17 of the MYBPC3 gene (NM_000256.3) The c.1624+2 T>C mutation has been reported previously in one patient diagnosed with HCM and was absent from 200 control chromosomes (Richard P et al., 2003). Additionally, c.1624+2 T>C was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This mutation destroys the canonical splice donor site in intron 17 and is predicted to cause abnormal gene splicing, leading 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.1624+2 T>C 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 (CirinoAet al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Invitae	RCV000707508	SCV000836609	likely pathogenic	Hypertrophic cardiomyopathy	2018-03-15	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 and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 12707239, 27532257). This variant is also described as IVS17+2t:11073c in the literature (PMID: 12707239). ClinVar contains an entry for this variant (Variation ID: 164107). 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). 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.
Laboratory for Molecular Medicine,Partners HealthCare 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.