Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000536804 | SCV000636244 | likely pathogenic | Charcot-Marie-Tooth disease, type I | 2018-05-16 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with glutamic acid at codon 103 of the MPZ protein (p.Gly103Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with severe CMT1 in a single family (PMID: 11445635). It was observed in two affected siblings and was absent in one unaffected sibling. This variant was also reported to be mosaic in the unaffected mother, and presumably arose de novo in this individual. This variant is also known as p.Gly74Glu in the literature. ClinVar contains an entry for this variant (Variation ID: 14187). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The observation of one or more missense substitutions at this codon (p.Gly103) in affected individuals suggests that this may be a clinically significant residue (PMID: 20456450). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| OMIM | RCV000015251 | SCV000035510 | pathogenic | Charcot-Marie-Tooth disease, demyelinating, type 1b | 2001-07-10 | no assertion criteria provided | literature only |