Submissions for variant NM_000257.4(MYH7):c.5229G>T (p.Glu1743Asp)

gnomAD frequency: 0.00001  dbSNP: rs149509691

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158687	SCV000208622	uncertain significance	not provided	2020-03-20	criteria provided, single submitter	clinical testing	Has not been previously reported in individuals with MYH7-related disease to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 181274; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23403236)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801865	SCV000941663	uncertain significance	Hypertrophic cardiomyopathy	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1743 of the MYH7 protein (p.Glu1743Asp). This variant is present in population databases (rs149509691, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181274). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV001525553	SCV001735698	uncertain significance	Cardiomyopathy	2023-04-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 1743 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 5/251482 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	RCV002336361	SCV002645306	uncertain significance	Cardiovascular phenotype	2023-08-11	criteria provided, single submitter	clinical testing	The p.E1743D variant (also known as c.5229G>T), located in coding exon 34 of the MYH7 gene, results from a G to T substitution at nucleotide position 5229. The glutamic acid at codon 1743 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002492627	SCV002781526	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	2021-09-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000158687	SCV003817657	uncertain significance	not provided	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001525553	SCV004239478	uncertain significance	Cardiomyopathy	2023-01-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001525553	SCV004829477	uncertain significance	Cardiomyopathy	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 1743 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 5/251482 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786430	SCV005399269	uncertain significance	Hypertrophic cardiomyopathy 1	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a 3C-VUS. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene (PMID:30623132). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a glutamic acid to an aspartic acid (exon 36). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (P) 0504 - Same amino acid change has been observed in mammals. (B) 0600 - Variant is located in an annotated domain or motif (Myosin tail domain; PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant is present at a low frequency in the population and has previously been described as a variant of uncertain significance (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign