Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000988073 | SCV001137645 | likely pathogenic | Charcot-Marie-Tooth disease type 4A | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000988073 | SCV003022103 | pathogenic | Charcot-Marie-Tooth disease type 4A | 2023-05-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 802414). This missense change has been observed in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 31827005, 33903021). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant Charcot-Marie-Tooth disease (PMID: 33903021); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 119 of the GDAP1 protein (p.Pro119Thr). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000988073 | SCV004100287 | likely pathogenic | Charcot-Marie-Tooth disease type 4A | 2023-09-29 | criteria provided, single submitter | clinical testing | Variant summary: GDAP1 c.355C>A (p.Pro119Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251466 control chromosomes. c.355C>A has been reported in the literature in at-least four individuals affected with Charcot-Marie Disease, either in trans along with a second pathogenic variant or at a homozygous state (example, Cavalcanti_2021, Cortese_2020, Figueiredo_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |