ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.541G>A (p.Val181Met) (rs863224064)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199084 SCV000251710 likely pathogenic not provided 2013-12-09 criteria provided, single submitter clinical testing p.Val181Met (GTG>ATG): c.541 G>A. The V181M missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V181M variant is a semi-conservative amino acid substitution as these residues share similar properties, but differ in size, charge, or other properties which may impact secondary structure. This substitution occurs at a position in the MFN2 protein that is highly conserved in mammals. In-silico analyses predict that V181M is damaging to the MFN2 protein. Therefore, V181M is interpreted to be a strong candidate for a disease-causing mutation. The variant is found in MITONUC-MITOP panel(s).
Invitae RCV001321536 SCV001512371 uncertain significance Charcot-Marie-Tooth disease, type 2 2020-01-21 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 181 of the MFN2 protein (p.Val181Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MFN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 214640). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C1). 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. 5

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