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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