Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000707568 | SCV000836669 | pathogenic | Giant axonal neuropathy 1 | 2023-02-04 | criteria provided, single submitter | clinical testing | This missense change has been observed in individuals with GAN-related conditions (PMID: 23248352, 23890932; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 269 of the GAN protein (p.Arg269Trp). This variant is present in population databases (rs776397915, gnomAD 0.005%). ClinVar contains an entry for this variant (Variation ID: 583275). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAN protein function. This variant disrupts the p.Arg269 amino acid residue in GAN. Other variant(s) that disrupt this residue have been observed in individuals with GAN-related conditions (PMID: 11062483, 12655563), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002406651 | SCV002675686 | likely pathogenic | Inborn genetic diseases | 2021-01-20 | criteria provided, single submitter | clinical testing | The p.R269W variant (also known as c.805C>T), located in coding exon 4 of the GAN gene, results from a C to T substitution at nucleotide position 805. The arginine at codon 269 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in trans with a second GAN alteration (c.732delT; p.I244Mfs*33) in two siblings and one unrelated individual with features of giant axonal neuropathy (Roth LA et al. Neuromuscul. Disord., 2014 Jan;24:48-55; Chakravorty S et al. Sci Rep, 2020 09;10:16184). The variant was also reported in the compound heterozygous state (along with c.1534G>A; p.R545H) in a Chinese girl with atypical giant axonal neuropathy phenotype presenting with features similar to Charcot-Marie-Tooth disease and lacking curled hair or intellectual disability (Xu M et al. J. Child Neurol., 2013 Oct;28:1316-9). In addition, a homozygous alteration at the same codon (c.806G>A; p.R269Q) has been reported in two brothers of German descent with reduced motor nerve conduction velocity, reduced sensory amplitudes, ataxia, areflexia, hypoesthesia, kinky hairs, scoliosis and giant axona on nerve biopsy (Bomont P et al. Hum. Mutat., 2003 Apr;21:446). 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 majority of available evidence to date, this variant is likely to be pathogenic. |
| Inherited Neuropathy Consortium | RCV000707568 | SCV000928492 | uncertain significance | Giant axonal neuropathy 1 | no assertion criteria provided | literature only | ||
| Inherited Neuropathy Consortium Ii, |
RCV000707568 | SCV004174505 | uncertain significance | Giant axonal neuropathy 1 | 2016-01-06 | no assertion criteria provided | literature only |