ClinVar Miner

Submissions for variant NM_014874.4(MFN2):c.1729A>G (p.Ile577Val)

gnomAD frequency: 0.00001  dbSNP: rs749606728
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236569 SCV000294199 uncertain significance not provided 2018-07-09 criteria provided, single submitter clinical testing The I577V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It 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. The I577V 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 where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000701448 SCV000830249 uncertain significance Charcot-Marie-Tooth disease type 2 2024-08-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 577 of the MFN2 protein (p.Ile577Val). This variant is present in population databases (rs749606728, gnomAD 0.002%). 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: 246602). 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%. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000236569 SCV001474577 uncertain significance not provided 2019-10-09 criteria provided, single submitter clinical testing The MFN2 c.1729A>G; p.Ile577Val variant (rs749606728), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 246602). This variant is found on only two chromosomes (2/113698 alleles) in the Genome Aggregation Database. The isoleucine at codon 577 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Ile577Val variant is uncertain at this time.

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