ClinVar Genomic variation as it relates to human health
NM_022041.4(GAN):c.944C>T (p.Pro315Leu)
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.
Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_022041.4(GAN):c.944C>T (p.Pro315Leu)
Variation ID: 245843 Accession: VCV000245843.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q23.2 16: 81357902 (GRCh38) [ NCBI UCSC ] 16: 81391507 (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 9, 2016 May 1, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022041.4:c.944C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071324.1:p.Pro315Leu missense NM_001377486.1:c.305C>T NP_001364415.1:p.Pro102Leu missense NC_000016.10:g.81357902C>T NC_000016.9:g.81391507C>T NG_009007.1:g.47937C>T LRG_242:g.47937C>T LRG_242t1:c.944C>T LRG_242p1:p.Pro315Leu Q9H2C0:p.Pro315Leu - Protein change
- P315L, P102L
- Other names
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- Canonical SPDI
- NC_000016.10:81357901:C:T
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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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0.00020 (G)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00015
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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
Help
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 |
709 | 838 |
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
Help
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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Likely pathogenic (1) |
criteria provided, single submitter
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Jun 24, 2021 | RCV000236891.6 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 11, 2024 | RCV000396992.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 18, 2022 | RCV002374390.3 | |
Uncertain significance (1) |
no assertion criteria provided
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Jun 1, 2023 | RCV003320356.2 |
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
(Jun 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000293006.12
First in ClinVar: Jul 25, 2016 Last updated: Mar 04, 2023 |
Comment:
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, … (more)
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) (less)
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Uncertain significance
(Apr 27, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000399018.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Jan 11, 2024)
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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: SCV000812327.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
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Uncertain significance
(Jan 18, 2022)
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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: SCV002684644.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Jun 01, 2023)
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no assertion criteria provided
Method: research
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Giant axonal neuropathy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neurogenomics Lab, Neuroscience Institute, University Of Cape Town
Accession: SCV003930345.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PM2_supporting: the highest population allele frequency in gnomAD v2.1.1 is 0.0007556 (0.076%; 8/10588 alleles in European Finnish population) and in gnomAD v3.1.2 is 0.0007556 (0.076%; … (more)
PM2_supporting: the highest population allele frequency in gnomAD v2.1.1 is 0.0007556 (0.076%; 8/10588 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. (less)
Sex: female
Geographic origin: South Africa
Comment on evidence:
Second variant is VUS GAN NP_071324.1:p.Gln94Ter.
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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: SCV004174535.1
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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New mutations, genotype phenotype studies and manifesting carriers in giant axonal neuropathy. | Houlden H | Journal of neurology, neurosurgery, and psychiatry | 2007 | PMID: 17578852 |
Clinical and molecular findings in patients with giant axonal neuropathy (GAN). | Bruno C | Neurology | 2004 | PMID: 14718689 |
Text-mined citations for rs144486241 ...
HelpRecord last updated May 01, 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.