Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000479637 | SCV000565035 | likely pathogenic | not provided | 2018-08-23 | criteria provided, single submitter | clinical testing | The c.786delG variant in the GDAP1 gene has been reported previously in the homozygous state in multiple affected siblings from two unrelated families segregating an autosomal recessive form of Charcot-Marie-Tooth syndrome; all tested family members who were heterozygous for the c.786delG variant were unaffected (Nelis et al., 2002). The c.786delG variant causes a frameshift starting with codon Phenylalanine 263, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 22 of the new reading frame, denoted p.Phe263LeufsX22. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.786delG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.786delG as a likely pathogenic variant; however, the possibility it may be a rare benign variant cannot be completely excluded. |
| Inherited Neuropathy Consortium | RCV000789157 | SCV000928509 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only | ||
| Invitae | RCV000456890 | SCV000544592 | pathogenic | Charcot-Marie-Tooth disease, type 4A | 2017-07-25 | criteria provided, single submitter | clinical testing | This sequence change deletes 1 nucleotide in exon 6 of the GDAP1 mRNA (c.786delG), causing a frameshift at codon 263. This creates a premature translational stop signal in the last exon of the GDAP1 mRNA (p.Phe263Leufs*22). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated GDAP1 protein. This variant has been previously reported to segregate with disease in a single family affected with autosomal recessive Charcot-Marie-Tooth disease (PMID: 12499475). A different truncation downstream of this variant (p.Arg341Glnfs*12) has been determined to be pathogenic (PMID: 25614874). This suggests that deletion of this region of the GDAP1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. |