ClinVar Genomic variation as it relates to human health
NM_001182.5(ALDH7A1):c.1513G>C (p.Gly505Arg)
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_001182.5(ALDH7A1):c.1513G>C (p.Gly505Arg)
Variation ID: 204852 Accession: VCV000204852.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q23.2 5: 126546376 (GRCh38) [ NCBI UCSC ] 5: 125882068 (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 Dec 19, 2017 Feb 20, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001182.5:c.1513G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001173.2:p.Gly505Arg missense NM_001201377.2:c.1429G>C NP_001188306.1:p.Gly477Arg missense NM_001202404.2:c.1321G>C NP_001189333.2:p.Gly441Arg missense NC_000005.10:g.126546376C>G NC_000005.9:g.125882068C>G NG_008600.2:g.54015G>C - Protein change
- G505R, G477R, G441R
- Other names
- p.G505R:GGC>CGC
- Canonical SPDI
- NC_000005.10:126546375:C:G
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00008
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00009
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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
Help
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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ALDH7A1 | - | - |
GRCh38 GRCh37 |
1066 | 1109 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (1) |
criteria provided, single submitter
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Mar 21, 2023 | RCV000186750.9 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV000545498.19 |
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
Help
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
Help
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
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Pyridoxine-dependent epilepsy
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893681.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(May 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pyridoxine-dependent epilepsy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002548157.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: ALDH7A1 c.1513G>C (p.Gly505Arg, also reported as p.Gly477Arg) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the … (more)
Variant summary: ALDH7A1 c.1513G>C (p.Gly505Arg, also reported as p.Gly477Arg) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251310 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALDH7A1 causing Pyridoxine-Dependent Epilepsy (8.8e-05 vs 0.0018), allowing no conclusion about variant significance. c.1513G>C has been reported in the literature in multiple compound heterozygous individuals affected with Pyridoxine-Dependent Epilepsy (e.g. Bennett_2009, Alfadhel_2012, Perez_2013, Kava_2020) and at least one homozygous individual (Perez_2013). These data indicate that the variant is very likely to be associated with disease. One publication using an E.coli expression system found that ALDH7A1 protein with the variant had less than 3% enzymatic activity (Coulter-Mackie_2012). Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 21, 2023)
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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: SCV000240317.17
First in ClinVar: Aug 07, 2015 Last updated: Apr 01, 2023 |
Comment:
Published functional studies demonstrate this variant abolishes ATQ enzyme activity (Coulter-Mackie et al., 2014); In silico analysis supports that this missense variant has a deleterious … (more)
Published functional studies demonstrate this variant abolishes ATQ enzyme activity (Coulter-Mackie et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31440721, 22784480, 19128417, 22728861, 30043187, 31980526, 32685344, 31589614, 24613284, 23350806, 20814824) (less)
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pyridoxine-dependent epilepsy
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004050028.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
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Pathogenic
(Mar 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pyridoxine-dependent epilepsy
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024317.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Pyridoxine-dependent epilepsy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000640311.10
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 505 of the ALDH7A1 protein (p.Gly505Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 505 of the ALDH7A1 protein (p.Gly505Arg). This variant is present in population databases (rs556400964, gnomAD 0.03%). This missense change has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 19128417, 20554659, 20814824, 23350806, 24942048). This variant is also known as c.1429G>C, p.Gly477Arg. ClinVar contains an entry for this variant (Variation ID: 204852). 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 expected to disrupt ALDH7A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 22784480). For these reasons, this variant has been classified as Pathogenic. (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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Beneficial outcome of early dietary lysine restriction as an adjunct to pyridoxine therapy in a child with pyridoxine dependant epilepsy due to Antiquitin deficiency. | Kava MP | JIMD reports | 2020 | PMID: 32685344 |
Callosal alterations in pyridoxine-dependent epilepsy. | Friedman SD | Developmental medicine and child neurology | 2014 | PMID: 24942048 |
Clinical, biochemical, and molecular studies in pyridoxine-dependent epilepsy. Antisense therapy as possible new therapeutic option. | Pérez B | Epilepsia | 2013 | PMID: 23350806 |
Overexpression of human antiquitin in E. coli: enzymatic characterization of twelve ALDH7A1 missense mutations associated with pyridoxine-dependent epilepsy. | Coulter-Mackie MB | Molecular genetics and metabolism | 2012 | PMID: 22784480 |
Variability of phenotype in two sisters with pyridoxine dependent epilepsy. | Alfadhel M | The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques | 2012 | PMID: 22728861 |
The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1. | Scharer G | Journal of inherited metabolic disease | 2010 | PMID: 20814824 |
Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). | Mills PB | Brain : a journal of neurology | 2010 | PMID: 20554659 |
Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients. | Bennett CL | Epilepsia | 2009 | PMID: 19128417 |
Text-mined citations for rs556400964 ...
HelpRecord last updated Mar 17, 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.