ClinVar Genomic variation as it relates to human health
NM_022041.4(GAN):c.1456G>A (p.Glu486Lys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_022041.4(GAN):c.1456G>A (p.Glu486Lys)
Variation ID: 5030 Accession: VCV000005030.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q23.2 16: 81365432 (GRCh38) [ NCBI UCSC ] 16: 81399037 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 1, 2015 Feb 14, 2024 Jun 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022041.4:c.1456G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071324.1:p.Glu486Lys missense NM_001377486.1:c.817G>A NP_001364415.1:p.Glu273Lys missense NC_000016.10:g.81365432G>A NC_000016.9:g.81399037G>A NG_009007.1:g.55467G>A LRG_242:g.55467G>A LRG_242t1:c.1456G>A LRG_242p1:p.Glu486Lys Q9H2C0:p.Glu486Lys - Protein change
- E486K, E273K
- Other names
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- Canonical SPDI
- NC_000016.10:81365431:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GAN | - | - |
GRCh38 GRCh37 |
704 | 832 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 29, 2023 | RCV000005333.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 19, 2019 | RCV002390092.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Feb 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Giant axonal neuropathy 1
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512623.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 strong, BP4 supporting
Geographic origin: Brazil
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Likely pathogenic
(Dec 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002695893.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.E486K variant (also known as c.1456G>A), located in coding exon 9 of the GAN gene, results from a G to A substitution at nucleotide … (more)
The p.E486K variant (also known as c.1456G>A), located in coding exon 9 of the GAN gene, results from a G to A substitution at nucleotide position 1456. The glutamic acid at codon 486 is replaced by lysine, an amino acid with similar properties. This variant was homozygous in a Tunisian family and compound heterozygous with a nonsense variant in a French family with giant axonal neuropathy (GAN) (Bomont P et al. Nat. Genet., 2000 Nov;26:370-4). Another affected individual was found to carry this alteration in trans with a microdeletion involving exons 3-11 of the GAN gene (Mahammad S et al. J. Clin. Invest., 2013 May;123:1964-75). This variant was not reported in the ExAC database, with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Giant axonal neuropathy 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001411255.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Nov 01, 2000)
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no assertion criteria provided
Method: literature only
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GIANT AXONAL NEUROPATHY 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025511.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2015 |
Comment on evidence:
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 … (more)
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. (less)
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Uncertain significance
(Jan 06, 2016)
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no assertion criteria provided
Method: literature only
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Giant axonal neuropathy 1
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174515.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Giant axonal neuropathy-associated gigaxonin mutations impair intermediate filament protein degradation. | Mahammad S | The Journal of clinical investigation | 2013 | PMID: 23585478 |
Giant axonal neuropathy caused by compound heterozygosity for a maternally inherited microdeletion and a paternal mutation within the GAN gene. | Buysse K | American journal of medical genetics. Part A | 2010 | PMID: 20949505 |
Intermediate filament aggregation in fibroblasts of giant axonal neuropathy patients is aggravated in non dividing cells and by microtubule destabilization. | Bomont P | Human molecular genetics | 2003 | PMID: 12668605 |
The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. | Bomont P | Nature genetics | 2000 | PMID: 11062483 |
Text-mined citations for rs119485088 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.