ClinVar Genomic variation as it relates to human health
NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)
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_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)
Variation ID: 217117 Accession: VCV000217117.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q24.1 10: 95633012 (GRCh38) [ NCBI UCSC ] 10: 97392769 (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 Jan 16, 2016 Aug 4, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002860.4:c.755G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002851.2:p.Arg252Gln missense NM_001017423.2:c.749G>A NP_001017423.1:p.Arg250Gln missense NM_001323412.2:c.422G>A NP_001310341.1:p.Arg141Gln missense NM_001323413.2:c.755G>A NP_001310342.1:p.Arg252Gln missense NM_001323414.2:c.755G>A NP_001310343.1:p.Arg252Gln missense NM_001323415.2:c.749G>A NP_001310344.1:p.Arg250Gln missense NM_001323416.2:c.422G>A NP_001310345.1:p.Arg141Gln missense NM_001323417.2:c.650G>A NP_001310346.1:p.Arg217Gln missense NM_001323418.2:c.416G>A NP_001310347.1:p.Arg139Gln missense NM_001323419.2:c.119G>A NP_001310348.1:p.Arg40Gln missense NC_000010.11:g.95633012C>T NC_000010.10:g.97392769C>T NG_012258.1:g.28799G>A P54886:p.Arg252Gln - Protein change
- R252Q, R139Q, R217Q, R141Q, R250Q, R40Q
- Other names
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- Canonical SPDI
- NC_000010.11:95633011: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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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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ALDH18A1 | - | - |
GRCh38 GRCh37 |
674 | 704 |
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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Pathogenic (2) |
criteria provided, single submitter
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Feb 8, 2018 | RCV000200959.13 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 23, 2021 | RCV000761744.33 | |
ALDH18A1 deficiency
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Pathogenic (1) |
criteria provided, single submitter
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Feb 17, 2020 | RCV001095737.12 |
Pathogenic (1) |
criteria provided, single submitter
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Jan 11, 2024 | RCV003765292.1 |
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
Help
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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Pathogenic
(Feb 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 9A
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000837685.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Number of individuals with the variant: 1
Clinical Features:
Unsteady gait (present) , Spastic paraparesis (present) , Spastic gait (present) , Scoliosis (present) , Quadriceps muscle atrophy (present) , Pes cavus (present) , Neonatal … (more)
Unsteady gait (present) , Spastic paraparesis (present) , Spastic gait (present) , Scoliosis (present) , Quadriceps muscle atrophy (present) , Pes cavus (present) , Neonatal respiratory distress (present) , Myopia (present) , Migraine (present) , Lumbar hyperlordosis (present) , Lower limb muscle weakness (present) , Low back pain (present) , Kyphoscoliosis (present) , Joint hypermobility (present) , Hyperreflexia (present) , Headache (present) , Hammertoe (present) , Generalized joint laxity (present) , Gait disturbance (present) , Fatigue (present) , Depressivity (present) (less)
Age: 30-39 years
Sex: female
Ethnicity/Population group: White
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2018-02-08
Testing laboratory interpretation: Pathogenic
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446467.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Spastic paraplegia (present)
Sex: male
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Likely pathogenic
(Apr 23, 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: SCV001783921.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Published functional studies suggest a damaging effect; specifically, in vitro functional expression assays show the mutant protein localizes normally to the mitochondria but low enzymatic … (more)
Published functional studies suggest a damaging effect; specifically, in vitro functional expression assays show the mutant protein localizes normally to the mitochondria but low enzymatic activity (Panza et al., 2016); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33573605, 26026163, 26297558, 31692161) (less)
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Pathogenic
(Feb 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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ALDH18A1 deficiency
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001251578.2
First in ClinVar: May 31, 2020 Last updated: Mar 04, 2023 |
Comment:
The ALDH18A1 c.755G>A (p.Arg252Gln) variant is a missense variant and has been reported in a heterozygous state in at least three unrelated affected individuals presenting … (more)
The ALDH18A1 c.755G>A (p.Arg252Gln) variant is a missense variant and has been reported in a heterozygous state in at least three unrelated affected individuals presenting with moderate to severe pyramidal signs, pes cavus, cataracts, gastro-oesophageal reflux, chronic cellulitis, and cortical atrophy (Panza et al. 2006; Coutelier et al. 2015). Segregation of the p.Arg252Gln variant with disease was observed in one family in seven affected members over three generations and was absent in all unaffected members (Panza et al. 2016). Functional studies with recombinant p.Arg252Gln variant protein demonstrated that the enzyme activity was reduced compared to wild type (Panza et al. 2016). In addition, the p.Arg252 residue lies in the glutamate-5-kinase domain and is predicted by modelling to lie within the active site (Panza et al. 2006; Coutelier et al. 2015). The p.Arg252Gln variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of ACMG criteria, the p.Arg252Gln variant is classified as pathogenic for ALDH18A1 deficiency. (less)
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant spastic paraplegia type 9
de Barsy syndrome Cutis laxa, autosomal dominant 3
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000812303.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 252 of the ALDH18A1 protein (p.Arg252Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 252 of the ALDH18A1 protein (p.Arg252Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 26026163, 26297558). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217117). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH18A1 protein function. Experimental studies have shown that this missense change affects ALDH18A1 function (PMID: 26297558). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000891929.26
First in ClinVar: Mar 31, 2019 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Aug 21, 2015)
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no assertion criteria provided
Method: literature only
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SPASTIC PARAPLEGIA 9A, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000255599.3
First in ClinVar: Oct 15, 2015 Last updated: Mar 18, 2023 |
Comment on evidence:
In affected members of a French family (FSP470) with spastic paraplegia-9A (SPG9A; 601162) and in a patient (patient 25014) with sporadic occurrence of the disorder, … (more)
In affected members of a French family (FSP470) with spastic paraplegia-9A (SPG9A; 601162) and in a patient (patient 25014) with sporadic occurrence of the disorder, Coutelier et al. (2015) identified a heterozygous c.755G-A transition (c.755G-A, NM_002860.3) in the ALDH18A1 gene, resulting in an arg252-to-gln (R252Q) substitution. Haplotype analysis excluded a founder effect. Functional studies of the variant were not performed. In affected members of an British family with autosomal dominant SPG9A, originally reported by Slavotinek et al. (1996), Panza et al. (2016) identified heterozygosity for the c.755G-A transition in the ALDH18A1 gene, resulting in an R252Q substitution at a highly conserved residue in the G5K domain. The mutation, which was found by candidate gene sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 142), 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in 446 control chromosomes. In vitro functional expression assays showed that the mutant protein localized normally to the mitochondria, but had low P5CS and G5K enzymatic activity; G5PR enzymatic activity was close to normal. Chromatography studies indicated that the mutation disturbed the architecture of the P5CS hexamer, putatively resulting in a dominant-negative effect. (less)
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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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ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism. | Panza E | Brain : a journal of neurology | 2016 | PMID: 26297558 |
Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. | Coutelier M | Brain : a journal of neurology | 2015 | PMID: 26026163 |
Cataracts, motor system disorder, short stature, learning difficulties, and skeletal abnormalities: a new syndrome? | Slavotinek AM | American journal of medical genetics | 1996 | PMID: 8779323 |
Text-mined citations for rs864321670 ...
HelpRecord last updated Aug 25, 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.