ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.748C>T (p.Arg250Trp) (rs373107074)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000653915 SCV000775805 likely pathogenic Charcot-Marie-Tooth disease, type 2 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 250 of the MFN2 protein (p.Arg250Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs373107074, ExAC 0.004%). This variant has been observed in individual(s) with autosomal recessive MFN2-related neuropathy/Charcot-Marie-Tooth disease type 2 (PMID:16714318, 26306937, 28660751). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has also been reported as heterozygous in two siblings affected with hereditary sensory and motor neuropathy and an individual affected with CMT2A, however a second rare variant in MFN2 was not found in these individuals (PMID: 26686600, 27862672). ClinVar contains an entry for this variant (Variation ID: 543219). 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, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091327 SCV001247287 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789065 SCV000928414 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Genesis Genome Database RCV000789065 SCV000999673 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research

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