ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.708G>A (p.Thr236=) (rs1557524867)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778182 SCV000914346 uncertain significance Charcot-Marie-Tooth disease, type 2 2017-09-01 criteria provided, single submitter clinical testing The MFN2 c.708G>A (p.Thr236=) variant has been reported in one study in which it is found in a heterozygous state in two related individuals from a family with Charcot-Marie-Tooth, Type 2 (CMT2). The proband developed neuropathy in his mid-twenties and exhibited numbness and aching in the distal lower limbs, erectile dysfunction, bilateral pes cavus, and progressive unsteady gait. Electrophysiological examination revealed severe sensory axonal neuropathy in the proband and mild motor and sensory axonal neuropathy in his son, who also met criteria for CMT2 (Martikainen et al. 2014). The p.Thr236= variant was absent from 295 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database. RT-PCR carried out on total RNA from the proband generated a wildtype protein and a truncated protein that lacked exon 7 and prematurely terminated in exon 8 (Martikainen et al. 2014). Based on the evidence, the p.Thr236 variant is classified as a variant of unknown significance but suspicious for pathogenicity for Charcot-Marie-Tooth, type 2. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000778182 SCV001375567 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-10-07 criteria provided, single submitter clinical testing This sequence change affects codon 236 of the MFN2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MFN2 protein. This variant also falls at the last nucleotide of exon 7 of the MFN2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with Charcot-Marie-Tooth disease type 2 (PMID: 24530046). ClinVar contains an entry for this variant (Variation ID: 631564). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 24530046). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Inherited Neuropathy Consortium RCV000789404 SCV000928759 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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