Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000697077 | SCV000825667 | pathogenic | Charcot-Marie-Tooth disease type 4A | 2023-03-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg282 amino acid residue in GDAP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12499475, 14561495, 18812441). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 574996). This missense change has been observed in individuals with autosomal recessive Charcot-Marie-Tooth disease (PMID: 21326314, 22206013, 28495047). This variant is present in population databases (rs375431837, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the GDAP1 protein (p.Arg282His). |
| Ambry Genetics | RCV002442480 | SCV002677474 | pathogenic | Inborn genetic diseases | 2022-01-26 | criteria provided, single submitter | clinical testing | The p.R282H pathogenic mutation (also known as c.845G>A), located in coding exon 6 of the GDAP1 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in the compound heterozygous state in multiple individuals with autosomal recessive GDAP1-related Charcot-Marie-Tooth disease (Abe A et al. J Hum Genet, 2011 May;56:364-8; Lin KP et al. PLoS One, 2011 Dec;6:e29393; Wu R et al. Front Neurosci, 2021 Jul;15:705277; Yoshimura A et al. Clin Genet, 2017 Sep;92:274-280). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive spectrum of Charcot-Marie-Tooth diseases when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant axonal Charcot-Marie-Tooth disease, type 2K is unclear. |
| Prevention |
RCV003938042 | SCV004754181 | pathogenic | GDAP1-related condition | 2024-01-25 | criteria provided, single submitter | clinical testing | The GDAP1 c.845G>A variant is predicted to result in the amino acid substitution p.Arg282His. This variant has been reported in individuals with autosomal recessive Charcot-Marie-Tooth disease (see for example, Abe et al. 2011. PubMed ID: 21326314; Lin et al. 2011. PubMed ID: 22206013; Fu et al. 2017. PubMed ID: 28495047; Wu et al. 2021. PubMed ID: 34366782). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. An alternative nucleotide change affecting the same amino acid (c.844C>T, p.Arg282Cys) has also been reported as causative for autosomal recessive Charcot-Marie-Tooth disease (Nelis et al. 2002. PubMed ID: 12499475; Sevilla et al. 2008. PubMed ID: 18812441; Correia and Santos. 2022. PubMed ID: 35316520). In summary, the c.845G>A (p.Arg282His) variant is interpreted as pathogenic. |
| Inherited Neuropathy Consortium | RCV000789687 | SCV000929062 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |