Submissions for variant NM_001005361.3(DNM2):c.868C>T (p.Arg290Trp)

gnomAD frequency: 0.00005  dbSNP: rs587778235

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766941	SCV000532701	uncertain significance	not provided	2016-11-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DNM2 gene. The R290W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R290W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R290W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821354	SCV000962108	uncertain significance	Charcot-Marie-Tooth disease dominant intermediate B	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 290 of the DNM2 protein (p.Arg290Trp). This variant is present in population databases (rs587778235, gnomAD 0.004%). This missense change has been observed in individual(s) with distal hereditary neuropathy (PMID: 33369814). ClinVar contains an entry for this variant (Variation ID: 133980). 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 DNM2 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.
Ambry Genetics	RCV002371955	SCV002684487	uncertain significance	Inborn genetic diseases	2021-11-02	criteria provided, single submitter	clinical testing	The p.R290W variant (also known as c.868C>T), located in coding exon 7 of the DNM2 gene, results from a C to T substitution at nucleotide position 868. The arginine at codon 290 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000766941	SCV003830491	uncertain significance	not provided	2019-03-21	criteria provided, single submitter	clinical testing
ITMI	RCV000120649	SCV000084810	not provided	not specified	2013-09-19	no assertion provided	reference population