ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.487G>C (p.Gly163Arg) (rs281865128)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205003 SCV000260072 pathogenic Charcot-Marie-Tooth disease, type I 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 163 of the MPZ protein (p.Gly163Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with disease in two families affected with Charcot-Marie-Tooth type 1 (CMT1) (PMID: 12207932, 15170620). A different nucleotide substitution (c.487G>A) that causes the same amino acid change as this variant (p.Gly163Arg) has also been reported in an individual affected with CMT1 as well as in a three members of a family affected with CMT1B (PMID: 8800924, 27088055). ClinVar contains an entry for this variant (Variation ID: 41022). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change that has been reported to segregate with disease and is absent from the general population. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000217802 SCV000279087 pathogenic not provided 2017-11-27 criteria provided, single submitter clinical testing The G163R missense pathogenic variant in the MPZ gene has been reported previously in four relatives with CMT1 (Street et al., 2002). Functional studies demonstrate that G163R (referred to as G134R in the publication due to alternative nomenclature) causes a loss of dimerization and oligomerization ability, thus impairing protein function (Plotkowski et al., 2007). A different nucleotide substitution (c.487 G>A) resulting in the same amino acid change (G163R) has been published in association with CMT (Stenson et al., 2014; IPN Mutation database). Additionally, many other missense variants in this region of the protein have been reported in the Human Gene Mutation Database in association with MPZ-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The G163R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000217802 SCV000333622 likely pathogenic not provided 2015-08-14 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000217802 SCV000614112 pathogenic not provided 2015-04-13 criteria provided, single submitter clinical testing
GeneReviews RCV000033919 SCV000057836 pathologic Charcot-Marie-Tooth disease, demyelinating, type 1b 2012-10-18 no assertion criteria provided curation Converted during submission to Pathogenic.
Inherited Neuropathy Consortium RCV000789486 SCV000928842 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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