ClinVar Miner

Submissions for variant NM_014874.4(MFN2):c.1327G>A (p.Val443Ile)

dbSNP: rs780450613
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001230600 SCV001403084 uncertain significance Charcot-Marie-Tooth disease type 2 2022-11-22 criteria provided, single submitter clinical testing This variant is present in population databases (rs780450613, gnomAD 0.008%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 443 of the MFN2 protein (p.Val443Ile). This variant has not been reported in the literature in individuals affected with MFN2-related conditions. 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. 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 expected to disrupt MFN2 protein function. ClinVar contains an entry for this variant (Variation ID: 957600).
Ambry Genetics RCV002379882 SCV002693015 uncertain significance Inborn genetic diseases 2021-02-18 criteria provided, single submitter clinical testing The p.V443I variant (also known as c.1327G>A), located in coding exon 11 of the MFN2 gene, results from a G to A substitution at nucleotide position 1327. The valine at codon 443 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant MFN2-related neuropathy; however, its contribution to the development of autosomal recessive MFN2-related neuropathy is uncertain.

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