Submissions for variant NM_000257.4(MYH7):c.3010C>G (p.Gln1004Glu)

gnomAD frequency: 0.00001  dbSNP: rs730880762

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158582	SCV000208517	uncertain significance	not provided	2018-02-07	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYH7 gene. The Q1004E variant has not been published as pathogenic or been reported as benign to our knowledge. It is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Q1004E variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as thee residues differ in some properties. However, in silico analysis, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Additional evidence is needed to clarify pathogenicity, including significant observation in affected individuals, informative segregation data, and functional evidence.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001065622	SCV001230589	uncertain significance	Hypertrophic cardiomyopathy	2022-11-15	criteria provided, single submitter	clinical testing	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. 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 expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 181209). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is present in population databases (rs730880762, gnomAD 0.007%). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1004 of the MYH7 protein (p.Gln1004Glu).
Color Diagnostics, LLC DBA Color Health	RCV001187172	SCV001353887	uncertain significance	Cardiomyopathy	2022-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 1004 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002433703	SCV002753332	uncertain significance	Cardiovascular phenotype	2019-12-19	criteria provided, single submitter	clinical testing	The p.Q1004E variant (also known as c.3010C>G), located in coding exon 22 of the MYH7 gene, results from a C to G substitution at nucleotide position 3010. The glutamine at codon 1004 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002478479	SCV002783563	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2022-04-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001187172	SCV004819194	uncertain significance	Cardiomyopathy	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with glutamic acid at codon 1004 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.