ClinVar Miner

Submissions for variant NM_001005360.2(DNM2):c.839C>T (p.Thr280Met) (rs202155679)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727032 SCV000705055 uncertain significance not provided 2017-01-26 criteria provided, single submitter clinical testing
GeneDx RCV000727032 SCV000293807 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing The T280M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The 1000 Genomes Project Consortium reports T280M was observed in 2/122 alleles from Americans of African ancestry in the Southwest USA. The T280M 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 in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000556861 SCV000640249 uncertain significance Charcot-Marie-Tooth disease, dominant intermediate B 2018-05-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 280 of the DNM2 protein (p.Thr280Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs202155679, ExAC 0.03%) but has not been reported in the literature in individuals with a DNM2-related disease. ClinVar contains an entry for this variant (Variation ID: 246310). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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