ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.296T>C (p.Ile99Thr)

dbSNP: rs1571819182
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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 RCV000812847 SCV000953175 pathogenic Charcot-Marie-Tooth disease, type I 2024-07-18 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 99 of the MPZ protein (p.Ile99Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type 1 (PMID: 9888385, 10093067, 11080236, 26310628). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 637349). 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 MPZ protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MPZ function (PMID: 29687021). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory, London Health Sciences Centre RCV000789473 SCV001336805 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789473 SCV000928829 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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