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.Ile736Val (c.2206 A>G) in MYH7 (NM_000257.2) The variant has been seen in at least 2 unrelated cases of HCM (not including this patient's family). There is no segregation data available. GeneDx notes that the variant is novel, however I was able to find reports of it online. The variant is listed in ClinVar with a submission from LMM (SCV000059428). The last reviewed in 2008 and classified it as a variant of uncertain significance. It looks like they saw this in one family, though specific phenotypic details are not provided. We have never seen this variant. The variant is also listed online in the Seidmans' database (http://genepath.med.harvard.edu/~seidman/outdated-mutdb/muts/MYH7_Ile736Val.html), noting their group has seen it in a patient with left ventricular wall thickness of 2.0 cm and a diagnosis of HCM. It is likely that the LMM case and Seidmans' case overlap, given how closely those two groups work together. Dr. Ackerman's group reported the variant in one patient in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.996). The isoleucine at codon 736 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Ile736Thr, which we classify as likely disease causing and p.Ile736Met, p.Ile736Leu) and nearby codons (A728V, A729P, I730T, P731L, P731S, G733R, G733E, Q734E, Q734P, G741A, G741R, G741W, A742E, E743D, per GeneDx report, referencing HGMD). In total the variant has not been seen in ~6700 published controls and individuals from publicly available population datasets. There is no variation at codon 736 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 3rd, 2014). The variant is listed in dbSNP (rs397516138), with the only submission being from LMM (as of July 3rd, 2014). The variant was not observed in the following published control samples: 200 (Bot et al 2014).