ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.506-2A>C

dbSNP: rs397516057
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000536316 SCV000059291 pathogenic Hypertrophic cardiomyopathy 2013-03-01 criteria provided, single submitter clinical testing The 506-2A>C variant in MYBPC3 has not been reported in the literature, but has been identified by our laboratory in 1 Caucasian individual with DCM (suspected burnt out HCM) and a family history of HCM, and segregated with disease in 2 aff ected relatives (LMM unpublished data). This variant occurs in the invariant reg ion (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splice variants in MYBPC3 ar e established as pathogenic for HCM. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon the p redicted impact to the protein.
Invitae RCV000536316 SCV000623613 pathogenic Hypertrophic cardiomyopathy 2018-11-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as 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). Experimental studies have shown that this intronic change leads to the loss of the canonical splice site and the use of an alternative splicing site, which caused the loss of the first seven nucleotides of exon 5 (PMID: 27834932). This particular variant has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (PMID: 25740977). ClinVar contains an entry for this variant (Variation ID: 42765). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 4 of the MYBPC3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Color Diagnostics, LLC DBA Color Health RCV001187127 SCV001353812 pathogenic Cardiomyopathy 2019-09-23 criteria provided, single submitter clinical testing This variant causes a A>C nucleotide substitution at the -2 position of intron 4 of the MYBPC3 gene. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 25740977, 27834932). This variant has been observed to segregate with disease in a family affected with hypertrophic cardiomyopathy (unpublished data by an external laboratory, Clinvar variation ID 42765). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A functional study using mRNA from the peripheral blood of an affected carrier has shown that this variant disrupts the canonical splice acceptor site and activates an alternative splice site, which results in a frameshift and premature protein truncation due to the loss of the first 7 nucleotides of exon 5 (PMID: 27834932). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

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