For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 24613284, 30043187). 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. This variant is also known as c.1348T>A (p.Cys450Ser). This missense change has been observed in individual(s) with ALDH7A1-related conditions (PMID: 17721876). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 478 of the ALDH7A1 protein (p.Cys478Ser).
ClinVar Genomic variation as it relates to human health
NM_001182.5(ALDH7A1):c.1432T>A (p.Cys478Ser)
Germline
Classification
Help
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.
(3)
Help
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.
Pathogenic
3
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001182.5(ALDH7A1):c.1432T>A (p.Cys478Ser)
Variation ID: 2136321 Accession: VCV002136321.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q23.2 5: 126549986 (GRCh38) [ NCBI UCSC ] 5: 125885678 (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 Feb 8, 2023 Jan 25, 2025 May 3, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001182.5:c.1432T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001173.2:p.Cys478Ser missense NM_001201377.2:c.1348T>A NP_001188306.1:p.Cys450Ser missense NM_001202404.2:c.1240T>A NP_001189333.2:p.Cys414Ser missense NC_000005.10:g.126549986A>T NC_000005.9:g.125885678A>T NG_008600.3:g.50405T>A - Protein change
- C478S, C414S, C450S
- Other names
- -
- Canonical SPDI
- NC_000005.10:126549985:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| ALDH7A1 | - | - |
GRCh38 GRCh37 |
1084 | 1127 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 3, 2024 | RCV003037113.5 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jul 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pyridoxine-dependent epilepsy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003439281.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 24613284, 30043187). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 24613284, 30043187). 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. This variant is also known as c.1348T>A (p.Cys450Ser). This missense change has been observed in individual(s) with ALDH7A1-related conditions (PMID: 17721876). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 478 of the ALDH7A1 protein (p.Cys478Ser). (less)
|
|
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Pathogenic
(Apr 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pyridoxine-dependent epilepsy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005076048.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
Variant summary: ALDH7A1 c.1432T>A (p.Cys478Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ALDH7A1 c.1432T>A (p.Cys478Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251368 control chromosomes (gnomAD). c.1432T>A has been reported in the literature in at least two compound heterozygous individuals who were affected with Pyridoxine-Dependent Epilepsy and carried a pathogenic variant in trans (e.g. Salomons_2007, Bok_2012, deRooy_2018, Coughlin_2019, Tseng_2022). In addition, the publications also reported experimental evidence evaluating an impact on protein function and demonstrated that the variant had about 14-20% activity when compared to the WT (e.g. Coulter-Mackie_2014, Coughlin_2019). The following publications have been ascertained in the context of this evaluation (PMID: 24613284, 17721876, 29661537, 30043187, 35782612, 22804844). ClinVar contains an entry for this variant (Variation ID: 2136321). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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|
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Pathogenic
(May 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pyridoxine-dependent epilepsy
Affected status: unknown
Allele origin:
germline
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV005672256.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
|
Comment:
Comment:
Variant summary: ALDH7A1 c.1432T>A (p.Cys478Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251368 control chromosomes (gnomAD). c.1432T>A has been reported in the literature in at least two compound heterozygous individuals who were affected with Pyridoxine-Dependent Epilepsy and carried a pathogenic variant in trans (e.g. Salomons_2007, Bok_2012, deRooy_2018, Coughlin_2019, Tseng_2022). In addition, the publications also reported experimental evidence evaluating an impact on protein function and demonstrated that the variant had about 14-20% activity when compared to the WT (e.g. Coulter-Mackie_2014, Coughlin_2019). The following publications have been ascertained in the context of this evaluation (PMID: 24613284, 17721876, 29661537, 30043187, 35782612, 22804844). ClinVar contains an entry for this variant (Variation ID: 2136321). Based on the evidence outlined above, the variant was classified as pathogenic.
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. |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 24613284, 30043187). 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. This variant is also known as c.1348T>A (p.Cys450Ser). This missense change has been observed in individual(s) with ALDH7A1-related conditions (PMID: 17721876). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 478 of the ALDH7A1 protein (p.Cys478Ser).
Comment:
Variant summary: ALDH7A1 c.1432T>A (p.Cys478Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251368 control chromosomes (gnomAD). c.1432T>A has been reported in the literature in at least two compound heterozygous individuals who were affected with Pyridoxine-Dependent Epilepsy and carried a pathogenic variant in trans (e.g. Salomons_2007, Bok_2012, deRooy_2018, Coughlin_2019, Tseng_2022). In addition, the publications also reported experimental evidence evaluating an impact on protein function and demonstrated that the variant had about 14-20% activity when compared to the WT (e.g. Coulter-Mackie_2014, Coughlin_2019). The following publications have been ascertained in the context of this evaluation (PMID: 24613284, 17721876, 29661537, 30043187, 35782612, 22804844). ClinVar contains an entry for this variant (Variation ID: 2136321). Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Pyridoxine-dependent epilepsy (PDE-ALDH7A1) in adulthood: A Dutch pilot study exploring clinical and patient-reported outcomes. | Tseng LA | Molecular genetics and metabolism reports | 2022 | PMID: 35782612 |
| The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy. | Coughlin CR 2nd | Journal of inherited metabolic disease | 2019 | PMID: 30043187 |
| Pyridoxine dependent epilepsy: Is late onset a predictor for favorable outcome? | de Rooy RLP | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2018 | PMID: 29661537 |
| Overexpression of recombinant human antiquitin in E. coli: partial enzyme activity in selected ALDH7A1 missense mutations associated with pyridoxine-dependent epilepsy. | Coulter-Mackie MB | Molecular genetics and metabolism | 2014 | PMID: 24613284 |
| Long-term outcome in pyridoxine-dependent epilepsy. | Bok LA | Developmental medicine and child neurology | 2012 | PMID: 22804844 |
| An intriguing "silent" mutation and a founder effect in antiquitin (ALDH7A1). | Salomons GS | Annals of neurology | 2007 | PMID: 17721876 |
Text-mined citations for this variant ...
HelpRecord last updated Jan 26, 2025
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.