ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs281865128
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Total submissions: 10
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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 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 163 of the MPZ protein (p.Gly163Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth type 1 (CMT1) (PMID: 12207932, 15170620). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41022). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MPZ protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000217802 SCV000279087 pathogenic not provided 2022-04-20 criteria provided, single submitter clinical testing Published functional studies demonstrate that G163R (referred to as G134R due to alternative nomenclature) causes a loss of dimerization and oligomerization ability, thus impairing protein function (Plotkowski et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 14711881, 26135405, 15170620, 34232518, 27614573, 12207932, 16414078, 18611372, 17915947, 30920665, 20461396, 26310628, 33179255, 33359733)
Eurofins Ntd Llc (ga) RCV000217802 SCV000333622 likely pathogenic not provided 2015-08-14 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000217802 SCV000614112 pathogenic not provided 2023-05-09 criteria provided, single submitter clinical testing This variant segregates with CMT in multiple families. This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. One other missense variant at this codon produces the same amino acid change as this variant (c.487G>A; p.Gly163Arg) and is also considered to be pathogenic. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been referred to as both p.Gly134Arg and p.Gly173Arg in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicate this variant (referred to as G134R) impairs protein oligomerization, thus impairing protein function (PMID: 17915947).
CeGaT Center for Human Genetics Tuebingen RCV000217802 SCV001249782 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000217802 SCV002051523 pathogenic not provided 2020-11-03 criteria provided, single submitter clinical testing PS3, PS4
Ambry Genetics RCV002326719 SCV002633857 pathogenic Inborn genetic diseases 2020-05-26 criteria provided, single submitter clinical testing The p.G163R pathogenic mutation (also known as c.487G>C), located in coding exon 4 of the MPZ gene, results from a G to C substitution at nucleotide position 487. The glycine at codon 163 is replaced by arginine, an amino acid with dissimilar properties. This variant has been shown to segregate with Charcot-Marie-Tooth (CMT) disease in multiple families (Eggers SD et al. Muscle Nerve, 2004 Jun;29:867-9; van Doormaal TP et al. Neuromuscul. Disord., 2016 Dec;26:837-840; Street VA et al. Neuromuscul. Disord., 2002 Oct;12:643-50). It has also been identified in a cohort of kindred descended from a single common ancestor (Caress JB et al. Muscle Nerve, 2019 07;60:62-66). A different nucleotide substitution (c.487G>A) that results in the same amino acid change (p.G163R) has been reported in association with CMT (Nelis E et al. Eur. J. Hum. Genet., 1996;4:25-33; Numakura C et al. Hum. Mutat., 2002 Nov;20:392-8; Werheid F et al. Brain Behav, 2016 04;6:e00451). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneReviews RCV000033919 SCV000057836 not provided Charcot-Marie-Tooth disease type 1B no assertion provided literature only
Inherited Neuropathy Consortium RCV000789486 SCV000928842 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Genesis Genome Database RCV000789486 SCV000999690 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research

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