ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.281G>A (p.Arg94Gln) (rs28940291)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000286431 SCV000255680 pathogenic not provided 2019-05-02 criteria provided, single submitter clinical testing Frequency data from large databases are of low quality and therefore uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Co-occurs with otherwise positive results less than expected. Damaging to protein function(s) relevant to disease mechanism. 2 de novo cases with parental identity confirmed.
GeneDx RCV000286431 SCV000329569 pathogenic not provided 2016-10-06 criteria provided, single submitter clinical testing The R94Q variant has been reported multiple times previously in association with autosomal dominant MFN2-related disorders (Zuchner et al., 2004; Klein et al., 2014; Bombelli et al., 2014). This substitution alters a conserved position predicted to be at beginning of the GTPase domain, which is essential for the function of the mitofusin protein (Guillet et al., 2011; Zuchner et al., 2004). The R94Q variant has been observed to induce a drastic decrease in ATP synthesis, suppress mitochondrial fusion and transport, and result in axonal degeneration (Guillet et al., 2011; Misko et al., 2012). Different missense variants at the same residue (R94W, R94P) as well as multiple missense variants in nearby residues (V91E, L92P, L92R, K98E) 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. Additionally, the R94Q 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. Therefore, we consider the R94Q variant to be pathogenic.
Invitae RCV000463055 SCV000547922 pathogenic Charcot-Marie-Tooth disease, type 2 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 94 of the mitofusin 2 protein (p.Arg94Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple unrelated individuals affected with Charcot-Marie-Tooth disease type 2 (CMT2) (PMID: 19889647, 17437620, 15064763, 25025039, 21508331, 15549395, 22492563), and in several families where it was observed to co-segregate with disease (PMID: 24604904, 16714318, 18996695). This variant has also been shown to arise de novo in an individual affected with CMT2 (PMID: 20350294). ClinVar contains an entry for this variant (Variation ID: 2268). Expression of the MFN2 protein containing the p.Arg94Gln variant has been shown to cause mitochondrial deficiencies (PMID: 21285398, 22442078, 17215403, 20335458) and locomotor impairments and gait defects mimicking the human CMT2A neuropathy phenotype in mice (PMID: 20418531). For these reasons, this sequence change has been classified as Pathogenic.
OMIM RCV000002356 SCV000022514 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2010-04-01 no assertion criteria provided literature only
Genesis Genome Database RCV000857091 SCV000999664 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research

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