ClinVar Miner

Submissions for variant NM_014874.4(MFN2):c.1061T>C (p.Val354Ala)

gnomAD frequency: 0.00002  dbSNP: rs1057518235
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413177 SCV000491692 uncertain significance not specified 2016-11-30 criteria provided, single submitter clinical testing The V354A variant in the MFN2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 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 V354A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar 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. We interpret V354A as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001850990 SCV002224340 uncertain significance Charcot-Marie-Tooth disease type 2 2024-09-30 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 354 of the MFN2 protein (p.Val354Ala). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MFN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 373126). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MFN2 protein function with a positive predictive value of 95%. 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.

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