Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute Of Human Genetics Munich, |
RCV000578374 | SCV000680247 | pathogenic | Charcot-Marie-Tooth disease dominant intermediate F | 2017-12-13 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000578374 | SCV000834280 | likely pathogenic | Charcot-Marie-Tooth disease dominant intermediate F | 2023-12-12 | 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 77 of the GNB4 protein (p.Gly77Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 34071515). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 488522). 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 GNB4 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |