rs776397915

Positions:

• chr16-81356956-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_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:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:2
• Conservation: PhyloP100: 1.22

Genes affected

GAN (HGNC:4137): (gigaxonin) This gene encodes a member of the cytoskeletal BTB/kelch (Broad-Complex, Tramtrack and Bric a brac) repeat family. The encoded protein plays a role in neurofilament architecture and is involved in mediating the ubiquitination and degradation of some proteins. Defects in this gene are a cause of giant axonal neuropathy (GAN). [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-81356957-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521988.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• PP5: Variant 16-81356956-C-T is Pathogenic according to our data. Variant chr16-81356956-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 583275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81356956-C-T is described in Lovd as [Pathogenic].

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: 3 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251446 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461108 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Giant axonal neuropathy 1 Pathogenic:1 Uncertain: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;D
Eigen	Benign	0.17
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.50	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.055	D
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.69		Loss of disorder (P = 0.012);Loss of disorder (P = 0.012);
MVP		0.83
MPC		0.56
ClinPred		0.86	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs776397915; hg19: chr16-81390561; COSMIC: COSV101666433;