Submissions for variant NM_004006.3(DMD):c.6847A>G (p.Ile2283Val)

gnomAD frequency: 0.00008  dbSNP: rs751145927

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256877	SCV001433369	likely benign	Dilated cardiomyopathy 1A	2019-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001586095	SCV001813546	uncertain significance	not provided	2019-05-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); At the protein level, in silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; At the mRNA level, in silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Ambry Genetics	RCV002366096	SCV002665010	uncertain significance	Cardiovascular phenotype	2020-09-18	criteria provided, single submitter	clinical testing	The p.I2283V variant (also known as c.6847A>G), located in coding exon 47 of the DMD gene, results from an A to G substitution at nucleotide position 6847. The isoleucine at codon 2283 is replaced by valine, an amino acid with highly similar properties. Based on data from gnomAD, the G allele has an overall frequency of 0.002% (4/205263) total alleles studied. The highest observed frequency was 0.01% (2/19050) of African alleles. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002570611	SCV003465764	uncertain significance	Duchenne muscular dystrophy	2024-05-08	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2283 of the DMD protein (p.Ile2283Val). This variant is present in population databases (rs751145927, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 978343). 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 DMD 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.
Natera, Inc.	RCV001830058	SCV002087816	uncertain significance	Becker muscular dystrophy; Duchenne muscular dystrophy; Cardiomyopathy; Dystrophin deficiency	2019-03-18	no assertion criteria provided	clinical testing