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.Glu1387Lys (c.4159 G>A) in the MYH7 gene. The variant has been seen in at least one unrelated cases of HCM (not including this patient's family). No segregation data is available. GeneDx notes the variant is novel, however I found a report of the variant in a poster from the 2010 European Society of Cardiology meeting (Waldmuller et al 2010, Http://spo.escardio.org/eslides/view.aspx?eevtid=40&fp=P2062). I could not find a report of this variant in any publications by the same group. In the poster they report observing the variant in one of 20 patents with "suspected familial HCM" who underwent sequencing of 17 cardiomyopathy associated genes. Ancestry is not noted, however the report is by a German group. No segregation data was reported. The same group also reported on the variant, very likely from the same case, at the 2010 Congress of the German Human Genetics Society (Waldmuller et al 2010). It is not in ClinVar. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.999). The glutamic acid at codon 1387 is completely conserved across species, as are neighboring amino acids. I could not find any other variants reported in association with disease at this codon, however there are variants reported in association with cardiomyopathy at nearby codons (p.Ala1379Thr (per the Seidman's database), p.Arg1382Gln, p.Arg1382Trp (per GeneDx report, referencing HGMD)). In total the variant has not been seen in ~6500 individuals from publicly available population datasets. There is no variation at codon 1387 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 23rd 2014).There is also no variation at this codon listed in dbSNP (as of July 24th, 2014).