ClinVar Miner

Submissions for variant NM_001005360.2(DNM2):c.1969C>T (p.Arg657Cys) (rs772920450)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236886 SCV000293278 uncertain significance not provided 2015-10-14 criteria provided, single submitter clinical testing The R657C variant in the DNM2 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The R657C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R657C variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (P647R and E650K) have been reported in the Human Gene Mutation Database in association with centronuclear myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R657C as a variant of uncertain significance
Invitae RCV000641107 SCV000762729 uncertain significance Charcot-Marie-Tooth disease, dominant intermediate B 2018-03-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 657 of the DNM2 protein (p.Arg657Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs772920450, ExAC 0.02%). This variant has not been reported in the literature in individuals with DNM2-related disease. ClinVar contains an entry for this variant (Variation ID: 246008). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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