Submissions for variant NM_000257.4(MYH7):c.5774G>A (p.Arg1925His)

gnomAD frequency: 0.00001  dbSNP: rs752553589

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464373	SCV000546199	uncertain significance	Hypertrophic cardiomyopathy	2024-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1925 of the MYH7 protein (p.Arg1925His). This variant is present in population databases (rs752553589, gnomAD 0.002%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476, 34194005). ClinVar contains an entry for this variant (Variation ID: 407171). 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%. This variant disrupts the p.Arg1925 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Fulgent Genetics, Fulgent Genetics	RCV000765156	SCV000896385	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	2021-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002356669	SCV002652198	uncertain significance	Cardiovascular phenotype	2024-07-03	criteria provided, single submitter	clinical testing	The p.R1925H variant (also known as c.5774G>A), located in coding exon 37 of the MYH7 gene, results from a G to A substitution at nucleotide position 5774. The arginine at codon 1925 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in a subject with dilated cardiomyopathy (DCM) (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV004000765	SCV004833792	uncertain significance	Cardiomyopathy	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1925 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 dilated cardiomyopathy (PMID: 32880476, 34194005). This variant has been identified in 2/251300 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.