ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.280C>T (p.Arg94Trp) (rs119103263)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000200468 SCV000230355 pathogenic not provided 2014-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000200468 SCV000251725 pathogenic not provided 2018-04-09 criteria provided, single submitter clinical testing The R94W missense mutation in the MFN2 gene has been reported previously as a de novo mutation in patients with early-onset, severe CMT2A (Zuchner et al., 2004; Zuchner et al., 2006; Brozkova et al., 2013). It was subsequently identified in a family with CMT6 and late-onset optic atrophy (Zuchner et al., 2006), and more recently it was reported in a patient with CMT1 (Hoyer et al., 2014). A different amino acid substitution at this same position (R94Q) and multiple nearby missense mutations (L92P, L92R, K98E, and A100G) have been reported in association with CMT. Therefore, the presence of the R94W mutation is consistent with a diagnosis of an MFN2-related neuropathy.
Invitae RCV000199279 SCV000253918 pathogenic Charcot-Marie-Tooth disease, type 2 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 94 of the MFN2 protein (p.Arg94Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs119103263, ExAC no frequency). This variant has been reported in multiple individuals affected with Charcot-Marie-Tooth disease (PMID: 16437557, 24126688, 19889647, 27549087, 26686600). ClinVar contains an entry for this variant (Variation ID: 2276). Experimental studies have shown that this missense change strongly impairs mitochondrial function in mice (PMID: 24862862). A different missense substitution at this codon (p.Arg94Gln) has been determined to be pathogenic (PMID: 15064763, 22442078, 21285398, 24604904). 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.
Athena Diagnostics Inc RCV000200468 SCV000255679 pathogenic not provided 2019-07-30 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/282876 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Damaging to protein function(s) relevant to disease mechanism. 2 de novo cases with parental identity confirmed.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415132 SCV000492868 pathogenic Short stature; Failure to thrive; Abnormality of the dentition; Microcephaly; Abnormality of dental enamel; Hyperpigmentation of the skin; Alopecia of scalp; Distal muscle weakness; EMG abnormality; Decreased body weight; Scarring alopecia of scalp; Abnormal blistering of the skin; Nail dystrophy; Scarring 2015-05-07 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV001173686 SCV001336790 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000190245 SCV001369441 pathogenic Hereditary motor and sensory neuropathy with optic atrophy 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000200468 SCV001433780 pathogenic not provided 2018-01-12 criteria provided, single submitter clinical testing The MFN2 c.280C>T; p.Arg94Trp has been reported multiple times in patients diagnosed with CMT disease (Zuchner 2004, Zuchner 2006, Cho 2007, Brožková 2013, Lassuthová 2016), and is classified as pathogenic in ClinVar (ID 2276). Functional studies have found defects in mitochondrial function in mice expressing this variant (Strickland 2014). Another variant affecting this amino acid (Arg94Gln) has also been demonstrated to be pathogenic (Zuchner 2005). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Based on the available information, the p.Arg94Trp variant is classified as pathogenic.
OMIM RCV000002364 SCV000022522 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2006-08-01 no assertion criteria provided literature only
OMIM RCV000190245 SCV000243769 pathogenic Hereditary motor and sensory neuropathy with optic atrophy 2006-08-01 no assertion criteria provided literature only

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