ClinVar

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. p.Asp239Glu (c.717 C>A) in the MYH7 gene. This variant has not previously been reported in the literature. Variation at nearby residues has been associated with HCM, supporting the functional importance of this region of the protein: Asn232Ser, Arg243His, Phe244Leu, Lys246Gln, Arg249Gln (Harvard Sarcomere Protein Gene Mutation Database). This is a conservative amino acid change, resulting in the replacement of an acidic, negatively-charged aspartic acid with an acidic, negatively-charged glutamic acid (which is identical except for one additional carbon lengthening the sidechain). The aspartic acid at this location is completely conserved across 32 mammalian species examined. The surrounding residues are also completely conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “possibly damaging”. In total the variant has not been seen in ~6900 individuals from publicly available population datasets; nor was it seen in Familion controls. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. There is also no variation at this residue listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org/index.htm) as of June 27, 2012. Familion reports that it did not observe the variant in over 400 internal controls who are “ethnically diverse” and presumed healthy.