Submissions for variant NM_000257.4(MYH7):c.3779G>A (p.Arg1260Gln)

gnomAD frequency: 0.00003  dbSNP: rs747308839

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000628951	SCV000749859	uncertain significance	Hypertrophic cardiomyopathy	2024-01-03	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 1260 of the MYH7 protein (p.Arg1260Gln). This variant is present in population databases (rs747308839, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of MYH7-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 525000). 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 not expected to disrupt MYH7 protein function with a negative 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	RCV001189996	SCV001357405	uncertain significance	Cardiomyopathy	2023-01-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1260 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 8/282810 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.
GeneDx	RCV001559512	SCV001781750	uncertain significance	not provided	2021-04-01	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 525000; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Fulgent Genetics, Fulgent Genetics	RCV002483767	SCV002788831	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	2021-09-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003302973	SCV003997496	uncertain significance	Cardiovascular phenotype	2023-06-04	criteria provided, single submitter	clinical testing	The p.R1260Q variant (also known as c.3779G>A), located in coding exon 26 of the MYH7 gene, results from a G to A substitution at nucleotide position 3779. The arginine at codon 1260 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an exome cohort (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 Jun;113:6701-6). 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.