Submissions for variant NM_000257.4(MYH7):c.3373G>C (p.Glu1125Gln)

dbSNP: rs730880904

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158858	SCV000208793	uncertain significance	not provided	2011-12-06	criteria provided, single submitter	clinical testing	This variant is denoted p.Glu1125Gln (E1125Q) at the protein level and c.3373 G>C at the cDNA level. The Glu1125Gln variant in the MYH7 gene has not been reported previously as a disease-causing mutation or as a rare benign polymorphism, to our knowledge. The Glu1125Gln variant results in a semi-conservative amino acid substitution of a negatively charged Glutamic acid with an uncharged, polar Glutamine at a position that is only conserved in mammalian species. In silico analysis predicts Glu1125Gln is probably damaging to the protein structure and function. Additionally, the NHLBI ESP Exome Variant Server reports Glu1125Gln was not observed in at least 5,032 individuals from Caucasian and African American backgrounds, indicating it is not a common benign polymorphism in these populations. Nevertheless, no mutations in neighboring codons have been reported in association with cardiomyopathy. In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine if Glu1125Gln is a disease-causing mutation or a rare benign polymorphism. The variant is found in HCM panel(s).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171204	SCV001333906	uncertain significance	Cardiomyopathy	2022-05-16	criteria provided, single submitter	clinical testing
Invitae	RCV002515077	SCV003032124	uncertain significance	Hypertrophic cardiomyopathy	2022-07-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1125 of the MYH7 protein (p.Glu1125Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 181383). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV003162664	SCV003911056	uncertain significance	Cardiovascular phenotype	2022-12-05	criteria provided, single submitter	clinical testing	The p.E1125Q variant (also known as c.3373G>C), located in coding exon 25 of the MYH7 gene, results from a G to C substitution at nucleotide position 3373. The glutamic acid at codon 1125 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.