ClinVar Miner

Submissions for variant NM_014874.4(MFN2):c.263T>C (p.Ile88Thr)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV001288131 SCV001475023 likely pathogenic not provided 2020-06-18 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One de novo case with parental identity confirmed.
Invitae RCV001381190 SCV001579484 pathogenic Charcot-Marie-Tooth disease, type 2 2020-03-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 88 of the MFN2 protein (p.Ile88Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of autosomal dominant Charcot-Marie-Tooth disease (Invitae). In at least one individual the variant was observed to be de novo. 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. This variant disrupts the p.Ile88 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26392352, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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