Submissions for variant NM_000257.4(MYH7):c.1351C>G (p.Gln451Glu)

dbSNP: rs730880871

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158798	SCV000208733	uncertain significance	not specified	2014-01-19	criteria provided, single submitter	clinical testing	p.Gln451Glu (CAG>GAG): c.1351 C>G in exon 14 of the MYH7 gene (NM_000257.2). The Q451E variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Q451E 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. Q451E 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. Mutations in nearby residues (K450E, K450T, R453C, R453H, R453L, R453S) have been reported in association with HCM, supporting the functional importance of this region of the protein. However, the Q451 residue is only conserved in mammal species. Additionally, in silico algorithms are not consistent in their predictions, but at least two concur that Q451E is benign to the protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if Q451E is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s).
Center for Human Genetics, University of Leuven	RCV000768518	SCV000886833	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000768518	SCV001374112	uncertain significance	Hypertrophic cardiomyopathy	2019-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine with glutamic acid at codon 451 of the MYH7 protein (p.Gln451Glu). 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 (ExAC no frequency). 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). 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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181344).