Description
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Val219Leu (c.655G>C) in exon 6 of the MYBPC3 gene (NM_000256.3) Given case data and functional studies we consider this variant likely disease causing. The variant has been seen in at least 15 unrelated cases of HCM (not including this patient). None of the studies below reported segregation data. The variant has been reported in multiple cases in the literature (Van Driest et al 2004, Kaski et al 2009, Ho et al 2009, Nunez et al 2013). Crehalet et al (2012) demonstrated that p.Val219Leu leads to complete skipping of exon 6. Many other variants in MYBPC3 that affect splicing have been implicated in cardiomyopathy. This is a conservative amino acid change with a nonpolar Valine replaced with a nonpolar Leucine at residue 219. Two variants at nearby residues of the variant (p.Asp228Asn and p.Gln208His) and another variant at the same residue (p.Val219Phe, Crehalet et al 2012) have been reported in association with HCM (CardioGenomics http://genepath.med.harvard.edu/ ). The Valine at codon 219 is highly, though not completely conserved (there is an Isoleucine in frogs). Of note, the variant affects the first base of exon 6, which is part of the splicing consensus sequence (and is most frequently a G). The Laboratory for Molecular Medicine performed in silico analysis with the program NNSplice and found the variant is predicted to affect splicing. In total this variant has not been seen in ~7500 published controls, laboratory controls, and publicly available general population samples. The variant was not observed in an internal sample of 400 presumably healthy controls of various ancestries at Familion Labs. Van Driest et al (2004) did not observe the variant in 100 Caucasian and 100 African American controls. Kaski et al (2009) did not identify the variant in 200 presumably healthy individuals of unspecified racial descent. GeneDx did not observe the variant in 400 Caucasian and African American controls. The variant is not currently listed in dbSNP or 1000 genomes and the variant is not listed in the NHLBI exome sequencing project, which currently includes data on ~4200 European Americans and ~2100 African Americans (as of March 10, 2015). There is one variation at codon 219 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~47,500 individuals of European, African, Latino and Asian descent (as of March 10, 2015). The amino acid substitution reported in exac was different, p.Val219Phe.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | not provided | not provided | not provided | not provided | | 15 | not provided | not provided | not provided |
