ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.337G>T (p.Val113Phe) (rs281865126)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657923 SCV000779690 uncertain significance not provided 2018-05-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MPZ gene. The V113F variant has been previously reported in an individual with demyelinating and axonal peripheral neuropathy, pes cavus, and pupillary light-near dissociation (Bienfait et al., 2002). However, this individual was also found to carry another variant (H81Y) on the same allele and parental studies were not performed. The V113F variant is not observed in large population cohorts (Lek et al., 2016). The V113F variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with MPZ-related disorders (Stenson et al., 2014). However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001208935 SCV001380350 uncertain significance Charcot-Marie-Tooth disease, type I 2019-08-20 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 113 of the MPZ protein (p.Val113Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the same chromosome (in cis) as another MPZ variant in an individual affected with peripheral neuropathy with demyelinating and axonal features (PMID: 11801400). ClinVar contains an entry for this variant (Variation ID: 41020, 208147). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
GeneReviews RCV000033917 SCV000057833 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1b 2015-03-26 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000789425 SCV000928780 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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