Submissions for variant NM_000257.4(MYH7):c.3455A>T (p.Glu1152Val)

gnomAD frequency: 0.00001  dbSNP: rs397516184

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035854	SCV000059505	uncertain significance	not specified	2014-08-07	criteria provided, single submitter	clinical testing	The Glu1152Val variant in MYH7 has been identified by our laboratory as homozygo us in 1 Caucasian adult with DCM as well as heterozygous in 1 sibling with borde rline left ventricular hypertrophy (Pugh 2014). Data from large population studi es is insufficient to assess the frequency of this variant. Glutamic acid (Glu) at position 1152 is highly conserved in mammals and across evolutionarily distan t species and the change to valine (Val) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogeni c prediction is estimated to be correct 94% of the time (Jordan 2011). In summar y, the clinical significance of the Glu1152Val variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706291	SCV000835331	uncertain significance	Hypertrophic cardiomyopathy	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1152 of the MYH7 protein (p.Glu1152Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 37652022). ClinVar contains an entry for this variant (Variation ID: 42961). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769451	SCV000900844	uncertain significance	Cardiomyopathy	2022-06-02	criteria provided, single submitter	clinical testing
GeneDx	RCV002259311	SCV002538767	uncertain significance	not provided	2022-06-08	criteria provided, single submitter	clinical testing	Reported in the apparent homozygous state in a patient with a personal and family history of dilated cardiomyopathy, but familial segregation information was not provided (Pugh et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 24503780)
Ambry Genetics	RCV002453300	SCV002616771	uncertain significance	Cardiovascular phenotype	2024-02-07	criteria provided, single submitter	clinical testing	The p.E1152V variant (also known as c.3455A>T), located in coding exon 25 of the MYH7 gene, results from an A to T substitution at nucleotide position 3455. The glutamic acid at codon 1152 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in a cardiomyopathy cohort and a genetic testing cohort; however, clinical details were limited (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;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.
Fulgent Genetics, Fulgent Genetics	RCV002477071	SCV002777261	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	2021-08-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002259311	SCV004236703	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000769451	SCV005430862	uncertain significance	Cardiomyopathy	2024-06-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 1152 of the MYH7 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.