ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.313C>A (p.Pro105Thr)

gnomAD frequency: 0.00001  dbSNP: rs121913609
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000223657 SCV000279620 likely pathogenic not provided 2016-01-18 criteria provided, single submitter clinical testing The P105T variant in the MPZ gene has been reported previously in two brothers with late-onset Charcot-Marie-Tooth type 2 and hearing impairment (Kabzinska et al., 2007). The P105T variant 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 P105T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. This substitution occurs at a position that is conserved across species. Additionally, multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001308867 SCV001498342 uncertain significance Charcot-Marie-Tooth disease, type I 2022-06-20 criteria provided, single submitter clinical testing 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. This variant disrupts the p.Pro105 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29465609). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14199). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 17663472). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 105 of the MPZ protein (p.Pro105Thr).
OMIM RCV000015263 SCV000035522 pathogenic Charcot-Marie-Tooth disease type 2J 2007-09-15 no assertion criteria provided literature only

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