ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.116A>C (p.His39Pro) (rs371856018)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201089 SCV000255795 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1b 2015-07-21 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000236108 SCV000614099 pathogenic not provided 2017-05-15 criteria provided, single submitter clinical testing
GeneDx RCV000236108 SCV000292950 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing The H39P pathogenic variant in the MPZ gene has been reported previously (using alternative nomenclature of H10P) in multiple unrelated individuals with late-onset neuropathy (CMT1B) (Shy et al., 2004; Souayah et al., 2007). It was also identified in a family of 10 individuals with hereditary motor and sensory neuropathy, and absent in 200 control individuals (Kilfoyle et al., 2006). Functional studies suggest that H39P may result in partial loss of function (Grandis et al., 2008). The H39P variant was not observed in large population cohorts (Lek et al, 2016). Additionally, many other missense variants in nearby residues have also been reported in the Human Gene Mutation Database in association with MPZ-related neuropathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, H39P is interpreted to be a pathogenic variant and its presence is consistent with the diagnosis of an MPZ-related disorder in this individual.
Invitae RCV000206430 SCV000261054 pathogenic Charcot-Marie-Tooth disease, type I 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 39 of the MPZ protein (p.His39Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is also known as p.His10Pro in the literature. This variant is not present in population databases (rs371856018, ExAC no frequency). This variant has been reported in multiple patients affected with Charcot-Marie-Tooth disease (CMT) (PMID: 14711881, 16844954, 26310628). In addition, it was found to segregate with CMT in two families (PMID: 16844954, 17602703). ClinVar contains an entry for this variant (Variation ID: 217232). Experimental studies have shown that this missense change leads to a decrease in MPZ-mediated intercellular adhesion in transfected cells (PMID: 18337304). For these reasons, this variant has been classified as Pathogenic.

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