Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000536804 | SCV000636244 | pathogenic | Charcot-Marie-Tooth disease, type I | 2022-10-05 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 11445635; Invitae). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly103 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been observed in individuals with MPZ-related conditions (PMID: 20456450), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects MPZ function (PMID: 29687021). 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. ClinVar contains an entry for this variant (Variation ID: 14187). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 103 of the MPZ protein (p.Gly103Glu). |
| Gene |
RCV001818160 | SCV002064159 | pathogenic | not provided | 2022-01-04 | criteria provided, single submitter | clinical testing | Reported previously in two sisters with severe CMT1 neuropathy; this variant was inherited from a mother who was mosaic for the G103E variant (Fabrizi et al., 2001); Published functional studies demonstrate that the unfolded protein response (UPR) and endoplasmic reticulum (ER) retention was significantly increased in the G103E variant when compared to wild type (Bai et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26310628, 20461396, 20456450, 28063088, 11445635, 29687021, 30076350, 24077912, 28902413) |
| Ambry Genetics | RCV002321483 | SCV002608253 | uncertain significance | Inborn genetic diseases | 2021-10-08 | criteria provided, single submitter | clinical testing | The p.G103E variant (also known as c.308G>A), located in coding exon 3 of the MPZ gene, results from a G to A substitution at nucleotide position 308. The glycine at codon 103 is replaced by glutamic acid, an amino acid with similar properties. This variant was detected in two siblings with Charcot-Marie-Tooth disease type 1 (CMT1), whose mother was also mosaic for the variant (Fabrizi GM et al. Neurology, 2001 Jul;57:101-5). This variant was also detected in an individual with Charcot-Marie-Tooth disease, type 1B (CMT1B); however, clinical details were limited (Sanmaneechai O et al. Brain, 2015 Nov;138:3180-92). Functional studies revealed this alteration led to abnormal accumulation in the ER and activation of the UPR (Bai Y et al. Ann Clin Transl Neurol, 2018 Apr;5:445-455). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. |
| OMIM | RCV000015251 | SCV000035510 | pathogenic | Charcot-Marie-Tooth disease type 1B | 2001-07-10 | no assertion criteria provided | literature only |