ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.356A>G (p.Tyr119Cys) (rs879254038)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000237035 SCV000293258 likely pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing The Y119C variant in the MPZ gene has not been reported previously in at least two families with adult-onset Charcot-Marie-Tooth (CMT) disease, with some individuals also exhibiting hearing loss (Senderek et al., 2000; Sanmaneechai et al., 2015). This variant is not observed in large population cohorts (Lek et al., 2016). The Y119C variant is a non-conservative amino acid substitution, within the extracellular immunoglobulin-like domain, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties (Sanmaneechai et al., 2015). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues (N116H, N116S, D118N, D121N, and N122S) have been reported in the Human Gene Mutation Database in association with CMT disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret Y119C as a likely pathogenic variant.
Invitae RCV000638165 SCV000759651 likely pathogenic Charcot-Marie-Tooth disease, type I 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 119 of the MPZ protein (p.Tyr119Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 10764043, 26310628, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 245997). This variant has been reported to have conflicting or insufficient data to determine the effect on MPZ protein function (PMID: 29687021). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000237035 SCV001249785 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000790120 SCV000929511 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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