Submissions for variant NM_000257.4(MYH7):c.2229G>C (p.Glu743Asp) (rs397516139)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158524	SCV000208459	likely pathogenic	not provided	2014-07-08	criteria provided, single submitter	clinical testing	p.Glu743Asp (GAG>GAC): c.2229 G>C in exon 20 of the MYH7 gene (NM_000257.2). The E743D variant in the MYH7 gene has been reported previously in association with HCM, and was not reported in 378 control alleles (Davis J et al., 2001). The E743D variant in MYH7 was reported in a 13-year-old male with early HCM and in his father who also had HCM. However, this 13-year-old patient also has two mutations in the MYLK gene inherited from his mother who also has HCM (Davis et al., 2001). In addition, the E743D variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. While the E743D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that when present is completely conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in nearby residues (G741R, G741W, G741A, A742E, L749Q) have been reported in association with familial cardiomyopathy, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in HCM panel(s).
OMIM	RCV000015166	SCV000035423	pathogenic	Cardiomyopathy, hypertrophic, midventricular, digenic	2001-11-30	no assertion criteria provided	literature only