Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000701205 | SCV000829995 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2022-09-23 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 180 of the GJB1 protein (p.Phe180Leu). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe180 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 10873293), which suggests that this may be a clinically significant amino acid residue. 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 GJB1 protein function. ClinVar contains an entry for this variant (Variation ID: 578250). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 16922730, 28448691; Invitae; external communication). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). |
| Athena Diagnostics Inc | RCV000991855 | SCV001143681 | likely pathogenic | not provided | 2019-05-22 | criteria provided, single submitter | clinical testing | Not found in the total gnomAD dataset, and the data is high quality (0/195627 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in a likely critical domain of the protein. |
| Gene |
RCV000991855 | SCV003930840 | likely pathogenic | not provided | 2023-05-25 | criteria provided, single submitter | clinical testing | A different nucleotide change resulting in the same missense variant (c.538 T>C p.F180L) has been reported in association with CMTX1 in published literature (Park et al., 2006); 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 16922730) |
| Inherited Neuropathy Consortium | RCV000789922 | SCV000929307 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |