rs776397915
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_022041.4(GAN):c.805C>T(p.Arg269Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R269Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_022041.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAN | NM_022041.4 | c.805C>T | p.Arg269Trp | missense_variant | 4/11 | ENST00000648994.2 | |
GAN | NM_001377486.1 | c.166C>T | p.Arg56Trp | missense_variant | 3/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAN | ENST00000648994.2 | c.805C>T | p.Arg269Trp | missense_variant | 4/11 | NM_022041.4 | P1 | ||
GAN | ENST00000648349.2 | c.*513C>T | 3_prime_UTR_variant, NMD_transcript_variant | 3/10 | |||||
GAN | ENST00000650388.1 | c.*162C>T | 3_prime_UTR_variant, NMD_transcript_variant | 2/9 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152090Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251446Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135906
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461108Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726914
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74278
ClinVar
Submissions by phenotype
Giant axonal neuropathy 1 Pathogenic:1Uncertain:2
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2023 | 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. - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 20, 2021 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at