Submissions for variant NM_000257.4(MYH7):c.5380C>G (p.Gln1794Glu)

dbSNP: rs397516247

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035962	SCV000059614	uncertain significance	not specified	2018-11-01	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000158697	SCV000208632	likely pathogenic	not provided	2012-04-27	criteria provided, single submitter	clinical testing	p.Gln1794Glu (CAG>GAG): c.5380 C>G in exon 37 of the MYH7 gene (NM_000257.2). The Gln1794Glu variant in the MYH7 gene has not been reported previously as a disease-causing mutation or as a benign variant, to our knowledge. Gln1794Glu results in a semi-conservative amino acid substitution of a neutral, polar Glutamine residue with a negatively charged Glutamic acid residue at a position that is conserved across species throughout evolution. In silico analysis predicts Gln1794Glu is damaging to the structure/function of the protein, and mutations affecting nearby residues (Asp1792Gly, Glu1801Gly) have been reported in association with DCM, supporting the functional importance of this region of the protein. The NHLBI ESP Exome Variant Server reports Gln1794Glu was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Therefore, Gln1794Glu is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in DCM panel(s).
Invitae	RCV000471537	SCV000546194	uncertain significance	Hypertrophic cardiomyopathy	2016-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with glutamic acid at codon 1794 of the MYH7 protein (p.Gln1794Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (rs397516247, ExAC no frequency). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 22464770). ClinVar contains an entry for this variant (Variation ID: 43067). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770470	SCV000901913	likely pathogenic	Cardiomyopathy	2023-06-28	criteria provided, single submitter	clinical testing