Submissions for variant NM_000257.4(MYH7):c.2666_2667delinsAA (p.Leu889Gln) (rs730880888)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158829	SCV000208764	likely pathogenic	not provided	2015-07-29	criteria provided, single submitter	clinical testing	The c.2666_2667delTCinsAA mutation results in a deletion of TC and insertion of AA, maintaining the reading frame and leading to a Leucine residue being replaced with a Glutamine residue at position 889 (L889Q). L889Q was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L889Q mutation is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Although this mutation has not been reported to our knowledge, a mutation in the same residue, L889H, has been reported in association with HCM in an affected preadolescent child (Kaski JP et al., 2009). Furthermore, missense mutations in nearby residues (Q882E, N885K, Q892K, E894G, A901G, A901P, E903G, E903K, C905R, C905F, D906G, L908V, I909M) have been reported in association with HCM, supporting the functional importance of this region of the protein. In summary, c.2666_2667delTCinsAA in the MYH7 gene is interpreted as a likely disease-causing mutation.