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

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205003	SCV000260072	pathogenic	Charcot-Marie-Tooth disease, type I	2020-10-20	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	2020-10-30	criteria provided, single submitter	clinical testing	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. 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 segregates with disease in multiple families. 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). This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Computational tools predict that this variant is damaging.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000217802	SCV001249782	pathogenic	not provided	2019-09-01	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
Genesis Genome Database	RCV000789486	SCV000999690	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research