Submissions for variant NM_000257.4(MYH7):c.4721G>A (p.Arg1574Gln)

gnomAD frequency: 0.00004  dbSNP: rs779715863

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217985	SCV000272052	uncertain significance	not specified	2015-05-14	criteria provided, single submitter	clinical testing	The p.Arg1574Gln variant in MYH7 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/66704 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Comput ational prediction tools and conservation analysis suggest that the p.Arg1574Gln variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, the clinical significance of the p.Arg 1574Gln variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000805571	SCV000945531	uncertain significance	Hypertrophic cardiomyopathy	2024-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1574 of the MYH7 protein (p.Arg1574Gln). This variant is present in population databases (rs779715863, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic and dilated cardiomyopathy (PMID: 27885498, 31983221, 37652022). ClinVar contains an entry for this variant (Variation ID: 228912). 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.
Color Diagnostics, LLC DBA Color Health	RCV001179801	SCV001344582	uncertain significance	Cardiomyopathy	2024-03-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1574 of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27885498) and in one individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 5/251410 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	RCV002338683	SCV002639239	uncertain significance	Cardiovascular phenotype	2021-11-09	criteria provided, single submitter	clinical testing	The p.R1574Q variant (also known as c.4721G>A), located in coding exon 32 of the MYH7 gene, results from a G to A substitution at nucleotide position 4721. The arginine at codon 1574 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in an individual from a hypertrophic cardiomyopathy cohort (Chida A et al. Heart Vessels, 2017 Jun;32:700-707). 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.
Revvity Omics, Revvity	RCV003137810	SCV003817673	uncertain significance	not provided	2021-03-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001179801	SCV004814372	uncertain significance	Cardiomyopathy	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1574 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27885498) and in an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 5/251410 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.