ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.310C>T (p.Arg104Trp) (rs119103268)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000002371 SCV000245506 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2013-05-10 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory in a 19-year-old male with speech delay, axonal motor sensory neuropathy, increased reflexes in upper extremities, absent reflexes in lower extremities
GeneDx RCV000197230 SCV000251709 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The R104W missense variant in the MFN2 gene has been reported previously as a de novo substitution in association with CMT2A and neuropathy (Brockmann et al., 2008; Genari et al., 2011; Del Bo et al., 2008, Tufano et al.,2015). The R104W variant 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. The R104W variant 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. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (A100G, T105M, T105A) have been reported in the Human Gene Mutation Database in association with MFN2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Fulgent Genetics,Fulgent Genetics RCV000515385 SCV000611283 pathogenic Charcot-Marie-Tooth disease, type 2A2A; Hereditary motor and sensory neuropathy with optic atrophy; Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2A2B 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000556047 SCV000657723 pathogenic Charcot-Marie-Tooth disease, type 2 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 104 of the MFN2 protein (p.Arg104Trp). 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 (rs119103268, ExAC no frequency). This variant has been reported in the heterozygous state in many individuals affected with Charcot-Marie-Tooth disease type 2 (CMT2) or early onset hereditary motor and sensory neuropathy (EOHMSN) (PMID: 18957892, 20008656, 21326314, 26382835, 25025039). In addition, this variant has been shown to arise de novo in multiple individuals affected with CMT2 or EOHMSN (PMID: 20008656, 18425620, 21840889, 21531138, 26307494) and has been reported to segregate with CMT2 in an affected family (PMID: 18946002). ClinVar contains an entry for this variant (Variation ID: 2281). 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. A different missense substitution at this codon (p.Arg104Leu) has been determined to be pathogenic (PMID: 22492563). 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 RCV000197230 SCV000706491 pathogenic not provided 2017-03-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV000144872 SCV001336788 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196400 SCV001367007 pathogenic Hyporeflexia; Generalized hypotonia; Distal muscle weakness 2019-09-04 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
OMIM RCV000002370 SCV000022528 pathogenic Hereditary motor and sensory neuropathy with optic atrophy 2008-12-09 no assertion criteria provided literature only
Dept. of Medical Genetics, Telemark Hospital Trust RCV000144872 SCV000172144 pathogenic Charcot-Marie-Tooth disease 2013-11-01 no assertion criteria provided research
OMIM RCV000002371 SCV000298223 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2008-12-09 no assertion criteria provided literature only
Institute of Human Genetics,Cologne University RCV000002371 SCV000787801 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2018-04-25 no assertion criteria provided clinical testing

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