Submissions for variant NM_000256.3(MYBPC3):c.2603-1G>C

dbSNP: rs977277400

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480283	SCV000567136	pathogenic	not provided	2015-07-01	criteria provided, single submitter	clinical testing	Although the c.2603-1 G>C variant has not been reported as a pathogenic variant or as a benignpolymorphism to our knowledge, this variant destroys the canonical splice acceptor site in intron 25 and ispredicted to cause abnormal gene splicing. The variant is predicted to lead to either an abnormal messagethat is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message isused for protein translation. Other splice site variants in the MYNPC3 gene have been reported inHGMD in association with cardiomyopathy (Stenson P et al., 2014). Furthermore, the c.2603-1 G>Csubstitution was not observed in approximately 6,200 individuals of European and African American ancestryin the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.2603 G>C in the MYBPC3 gene is interpreted as a pathogenic variant.
Ambry Genetics	RCV000622650	SCV000741686	likely pathogenic	Inborn genetic diseases	2016-09-08	criteria provided, single submitter	clinical testing
Invitae	RCV001379446	SCV001577249	likely pathogenic	Hypertrophic cardiomyopathy	2021-03-16	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. 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). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510, 27532257, 30297972). ClinVar contains an entry for this variant (Variation ID: 419380). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 25 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798856	SCV002042174	likely pathogenic	Cardiomyopathy	2019-08-26	criteria provided, single submitter	clinical testing