16-81357902-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP5 BP4

The NM_022041.4(GAN):c.944C>T(p.Pro315Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000202 in 1,613,632 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P315R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: GAN NM_022041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: 5.72

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a repeat Kelch 1 (size 52) in uniprot entity GAN_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_022041.4
• PP5: Variant 16-81357902-C-T is Pathogenic according to our data. Variant chr16-81357902-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245843.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}. Variant chr16-81357902-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3408289).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAN	NM_022041.4	c.944C>T	p.Pro315Leu	missense_variant	5/11	ENST00000648994.2
GAN	NM_001377486.1	c.305C>T	p.Pro102Leu	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAN	ENST00000648994.2	c.944C>T	p.Pro315Leu	missense_variant	5/11		NM_022041.4	P1
GAN	ENST00000648349.2	c.*652C>T		3_prime_UTR_variant, NMD_transcript_variant	4/10
GAN	ENST00000650388.1	c.*301C>T		3_prime_UTR_variant, NMD_transcript_variant	3/9

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000756

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251490 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135918

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: 0.0000327

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000211 AC: 309 AN: 1461516 Hom.: 2 Cov.: 31 AF XY: 0.000202 AC XY: 147 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000918

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74296

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000756

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Giant axonal neuropathy 1 Pathogenic:1 Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 315 of the GAN protein (p.Pro315Leu). This variant is present in population databases (rs144486241, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with giant axonal neuropathy (PMID: 14718689, 17578852; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 245843). 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 not expected to disrupt GAN protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The GAN c.944C>T (p.Pro315Leu) missense variant has been reported in two studies in which it is found in a compound heterozygous state in two patients with giant axonal neuropathy, one with a missense variant on the second allele, and one with a frameshift variant (Bruno et al. 2004; Houlden et al. 2007). The p.Pro315Leu variant was also found in a heterozygous state in one of the parents diagnosed with mild multiple sclerosis. The p.Pro315Leu variant was absent from 100 controls but is reported at a frequency of 0.000907 in the European (Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Pro315Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for giant axonal neuropathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2021

The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17256086, 17578852, 14718689, 21356581, 23890932) -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

The p.P315L variant (also known as c.944C>T), located in coding exon 5 of the GAN gene, results from a C to T substitution at nucleotide position 944. The proline at codon 315 is replaced by leucine, an amino acid with similar properties. In one individual with giant axonal neuropathy, this alteration was detected in trans with a frameshift alteration in GAN (Houlden H et al. J Neurol Neurosurg Psychiatry, 2007 Nov;78:1267-70). This alteration was also detected as compound heterozygous with a missense alteration in GAN In another individual with giant axonal neuropathy; however, the phase of the variants was unknown (Bruno C et al. Neurology, 2004 Jan;62:13-6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Giant axonal neuropathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

May 22, 2024

PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.0008910 (0.089%; 57/63974 alleles in European Finnish population) and in gnomAD v3.1.2 is 0.0007556 (0.076%; 1/10588 alleles in European Finnish population) and the variant is absent from an internal database of 1074 alleles. PS4_supporting: variant identified in 2 unrelated probands with consistent phenotype for disorder (PMID 14718689, PMID 17578852). PP3 not met: REVEL score is 0.49. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
Sift4G	Benign	0.065	T;.
Polyphen		0.81	P;P
Vest4		0.89
MVP		0.92
MPC		0.18
ClinPred		0.32	T
GERP RS		5.9
Varity_R		0.40
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144486241; hg19: chr16-81391507; COSMIC: COSV73720960;