Submissions for variant NM_000257.4(MYH7):c.2696C>A (p.Ala899Glu)

dbSNP: rs730880753

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158561	SCV000208496	likely pathogenic	not provided	2013-12-02	criteria provided, single submitter	clinical testing	p.Ala899Glu (GCA>GAA): c.2696 C>A in exon 23 of the MYH7 gene (NM_000257.2). The Ala899Glu variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Ala899Glu variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The Ala899 residue is conserved through mammals and fowl. However, in silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. Nevertheless, mutations in nearby residues (Ala893Val, Glu894Gly, Ala901Pro, Ala901Gly, Glu903Lys, Glu903Gly) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Furthermore, the Ala899Glu variant 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. In summary, while Ala899Glu is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM-CRDM panel(s).
Invitae	RCV001850215	SCV002286758	uncertain significance	Hypertrophic cardiomyopathy	2022-10-01	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 181199). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH7 protein function. This missense change has been observed in individual(s) with dilated cardiomyopathy (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 899 of the MYH7 protein (p.Ala899Glu).