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 | 2019-12-23 | 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. |
Gene |
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, |
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 | |
Ce |
RCV000217802 | SCV001249782 | pathogenic | not provided | 2019-09-01 | criteria provided, single submitter | clinical testing | |
Gene |
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 |