ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.311G>T (p.Arg104Leu) (rs863224068)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532246 SCV000657724 pathogenic Charcot-Marie-Tooth disease, type 2 2017-03-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 104 of the MFN2 protein (p.Arg104Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. It also falls at the last nucleotide of exon 4 of the MFN2 coding sequence. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Charcot-Marie-Tooth disease (PMID: 22492563). ClinVar contains an entry for this variant (Variation ID: 214651). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Arg104Trp) has been determined to be pathogenic (PMID: 26307494, 18425620). This suggests that the arginine residue is critical for MFN2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000711275 SCV000705951 uncertain significance not provided 2017-04-07 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000711275 SCV000841611 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789063 SCV000928412 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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