ClinVar Miner

Submissions for variant NM_014874.4(MFN2):c.404G>A (p.Arg135Gln)

gnomAD frequency: 0.00001  dbSNP: rs1443036026
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000694043 SCV000822469 uncertain significance Charcot-Marie-Tooth disease type 2 2024-02-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 135 of the MFN2 protein (p.Arg135Gln). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 29858556; Invitae). ClinVar contains an entry for this variant (Variation ID: 549683). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MFN2 protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
GeneDx RCV004721534 SCV005327232 uncertain significance not provided 2023-06-29 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 24863639, 32709422, 29858556, 32618126)
Institute of Human Genetics, Cologne University RCV000664229 SCV000787794 likely pathogenic Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; 2018-04-25 no assertion criteria provided clinical testing

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