NM_022041.4(GAN):c.1456G>A (p.Glu486Lys) AND Giant axonal neuropathy 1

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jun 29, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000005333.15

Allele description [Variation Report for NM_022041.4(GAN):c.1456G>A (p.Glu486Lys)]

NM_022041.4(GAN):c.1456G>A (p.Glu486Lys)

Gene:

GAN:gigaxonin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q23.2

Genomic location:

Preferred name:

NM_022041.4(GAN):c.1456G>A (p.Glu486Lys)

HGVS:

NC_000016.10:g.81365432G>A
NG_009007.1:g.55467G>A
NM_001377486.1:c.817G>A
NM_022041.4:c.1456G>AMANE SELECT
NP_001364415.1:p.Glu273Lys
NP_071324.1:p.Glu486Lys
NP_071324.1:p.Glu486Lys
LRG_242t1:c.1456G>A
LRG_242:g.55467G>A
LRG_242p1:p.Glu486Lys
NC_000016.9:g.81399037G>A
NM_022041.3:c.1456G>A
Q9H2C0:p.Glu486Lys

Protein change:

E273K; GLU486LYS

Links:

UniProtKB: Q9H2C0#VAR_010757; OMIM: 605379.0001; dbSNP: rs119485088

NCBI 1000 Genomes Browser:

rs119485088

Molecular consequence:

NM_001377486.1:c.817G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_022041.4:c.1456G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Giant axonal neuropathy 1 (GAN1)
Synonyms:: GIANT AXONAL NEUROPATHY 1, AUTOSOMAL RECESSIVE
Identifiers:: MONDO: MONDO:0009749; MedGen: C1850386; Orphanet: 643; OMIM: 256850

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025511	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2000)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001411255	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 29, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11062483, 20949505, 28492532
SCV002512623	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004174515	Inherited Neuropathy Consortium Ii, University Of Miami	no assertion criteria provided	Uncertain significance (Jan 6, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Giant axonal neuropathy caused by compound heterozygosity for a maternally inherited microdeletion and a paternal mutation within the GAN gene.

Buysse K, Vergult S, Mussche S, Ceuterick-de Groote C, Speleman F, Menten B, Lissens W, Van Coster R.

Am J Med Genet A. 2010 Nov;152A(11):2802-4. doi: 10.1002/ajmg.a.33508.

PubMed [citation]

PMID:: 20949505

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000025511.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Bomont et al. (2000) found a glu486-to-lys (E486K) mutation of the GAN gene associated with giant axonal neuropathy (GAN1; 256850) in a Tunisian and a northern French family. They concluded that these corresponded to distinct mutational events because the mutation affected a CpG dinucleotide (CG to CA) and the associated haplotypes were different.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001411255.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 5030). This missense change has been observed in individual(s) with giant axonal neuropathy (PMID: 11062483, 20949505). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs119485088, gnomAD 0.004%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 486 of the GAN protein (p.Glu486Lys).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512623.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 strong, BP4 supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Inherited Neuropathy Consortium Ii, University Of Miami, SCV004174515.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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