ClinVar Miner

Submissions for variant NM_007289.4(MME):c.1946T>C (p.Ile649Thr)

dbSNP: rs184666602
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489719 SCV000576939 uncertain significance not provided 2024-07-15 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Milley2019[Thesis])
Labcorp Genetics (formerly Invitae), Labcorp RCV000489719 SCV002177492 likely pathogenic not provided 2024-12-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 649 of the MME protein (p.Ile649Thr). This variant is present in population databases (rs184666602, gnomAD 0.01%). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (internal data). ClinVar contains an entry for this variant (Variation ID: 426487). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MME protein function. This variant disrupts the p.Ile649 amino acid residue in MME. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33144514; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000489719 SCV005410443 uncertain significance not provided 2024-01-04 criteria provided, single submitter clinical testing PP3, PM1, PM2_moderate

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