ClinVar Miner

Submissions for variant NM_014874.4(MFN2):c.746C>T (p.Ser249Phe) (rs794729198)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000184017 SCV000292313 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2015-09-17 criteria provided, single submitter research This variant has been previously reported as disease-causing and was found in a 3.5 year old patient with peripheral neuropathy.
Invitae RCV001245336 SCV001418618 likely pathogenic Charcot-Marie-Tooth disease, type 2 2019-10-10 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 249 of the MFN2 protein (p.Ser249Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 21326314, 26378787, 26801520). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 202171). 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 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.
Mendelics RCV000184017 SCV000236548 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2013-02-14 no assertion criteria provided clinical testing
Inherited Neuropathy Consortium RCV000789360 SCV000928715 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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