ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.1090C>T (p.Arg364Trp) (rs119103265)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198024 SCV000251715 pathogenic not provided 2017-12-21 criteria provided, single submitter clinical testing The R364W pathogenic variant in the MFN2 gene has been reported previously in association with hereditary motor and sensory neuropathy type VI and CMT2A (Zuchner et al., 2006; Chung et al., 2006; Gowrisankaran et al., 2011). Additionally, two different missense pathogenic variants at this same position (R364Q and R364P) have been reported in association with MFN2-related disorders (Stenson et al., 2014). R364W was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R364W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species.
Invitae RCV000195560 SCV000253916 pathogenic Charcot-Marie-Tooth disease, type 2 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 364 of the MFN2 protein (p.Arg364Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in any individuals in the large population databases (ExAC no frequency). This variant has been reported in multiple individuals with autosomal dominant Charcot-Marie-Tooth disease type 2A and hereditary motor and sensory neuropathy type VI. These individuals have typically presented with a severe, early onset phenotype. Individuals with this variant have been observed with and without optic atrophy (PMID: 16437557, 16835246, 22492563, 21707411, 22206013, 21508331, 25802885, 28063088, 27549087, 25448007). ClinVar contains an entry for this variant (Variation ID: 2278). Codon 364 is located in the highly conserved R3 region of the MFN2 protein and has been described as a mutation hotspot. Several other pathogenic missense changes have been observed at this site (PMID: 22206013, 21508331). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000023711 SCV000255674 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2014-11-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000198024 SCV001247289 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing
OMIM RCV000002367 SCV000022525 pathogenic Hereditary motor and sensory neuropathy with optic atrophy 2006-08-01 no assertion criteria provided literature only
Northcott Neuroscience Laboratory, ANZAC Research Institute RCV000023711 SCV000188691 pathogenic Charcot-Marie-Tooth disease, type 2A2A no assertion criteria provided not provided Converted during submission to Pathogenic.
OMIM RCV000023711 SCV000298221 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2006-08-01 no assertion criteria provided literature only
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital,College of Medicine, The Catholic University of Korea RCV000023711 SCV000882757 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2019-02-11 no assertion criteria provided research
Genesis Genome Database RCV000857103 SCV000999677 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research
Genesis Genome Database RCV000857104 SCV000999678 uncertain significance Charcot-Marie-Tooth disease type 4 2019-08-14 no assertion criteria provided research

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