Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001227710 | SCV001400080 | uncertain significance | Charcot-Marie-Tooth Neuropathy X | 2019-10-28 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine with threonine at codon 40 of the GJB1 protein (p.Ala40Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Charcot-Marie-Tooth disease (PMID: 12536289). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ala40 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8800924, 28768847, 12460545). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Inherited Neuropathy Consortium | RCV000789262 | SCV000928614 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |