Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000527122 | SCV000644075 | uncertain significance | Charcot-Marie-Tooth disease, type 4A | 2018-02-21 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine with arginine at codon 218 of the GDAP1 protein (p.Gln218Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a GDAP1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Gln218Glu) has been determined to be likely pathogenic (PMID: 18231710, 26525999, 23628762). This suggests that the glutamine residue is critical for GDAP1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant has uncertain impact on GDAP1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |