VCV000374140.35 - ClinVar

NM_001182.5(ALDH7A1):c.1566-1G>T

Germline

Classification

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.

(8)

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

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.1566-1G>T

Variation ID: 374140 Accession: VCV000374140.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q23.2 5: 126545020 (GRCh38) [ NCBI UCSC ] 5: 125880712 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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, 2017	Dec 22, 2024	Oct 31, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001182.5:c.1566-1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001201377.2:c.1482-1G>T		splice acceptor
NM_001202404.2:c.1374-1G>T		splice acceptor
NC_000005.10:g.126545020C>A
NC_000005.9:g.125880712C>A
NG_008600.3:g.55371G>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000005.10:126545019:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA3389347 dbSNP: rs140845195 VarSome

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
Gene	OMIM	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.
Seizure Ventriculomegaly	Pathogenic (1)	criteria provided, single submitter	Jan 15, 2015	RCV000414868.3
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 31, 2023	RCV000523518.21
Pyridoxine-dependent epilepsy	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 29, 2023	RCV000558837.15
ALDH7A1-related disorder	Pathogenic (1)	no assertion criteria provided	Jan 2, 2024	RCV003902460.3
Pyridoxine-dependent epilepsy caused by ALDH7A1 mutant	Pathogenic (1)	criteria provided, single submitter	Sep 4, 2023	RCV003993949.1

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 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.
Pathogenic (Jan 15, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizure Ventriculomegaly Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492930.1 First in ClinVar: Jan 16, 2017 Last updated: Jan 16, 2017
Pathogenic (Nov 05, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pyridoxine-dependent epilepsy Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001370466.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pyridoxine-dependent epilepsy Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004049973.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023
Pathogenic (Oct 31, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617379.3 First in ClinVar: Dec 19, 2017 Last updated: Nov 25, 2023	Comment: Observed in the homozygous state, with a pathogenic variant on the opposite allele (in trans), or with a second ALDH7A1 variant, phase unknown, in individuals … (more) Observed in the homozygous state, with a pathogenic variant on the opposite allele (in trans), or with a second ALDH7A1 variant, phase unknown, in individuals with pyridoxine-dependent epilepsy in the published literature and not observed in homozygous state in controls (PMID: 30043187, 17068770); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Previously reported as c.1482-1 G>T due to alternative nomenclature; This variant is associated with the following publications: (PMID: 31589614, 29286531, 31990480, 17068770, 36011376, 30043187, 31440721, 31623504) (less)
Pathogenic (Aug 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Pyridoxine-dependent epilepsy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000640315.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 28492532‚ 17576681‚ 9536098‚ 23350806‚ 17068770 Comment: This sequence change affects an acceptor splice site in intron 17 of the ALDH7A1 gene. RNA analysis indicates that disruption of this splice site induces … (more) This sequence change affects an acceptor splice site in intron 17 of the ALDH7A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 5 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 18 (PMID: 23350806). ClinVar contains an entry for this variant (Variation ID: 374140). This variant is also known as c.1482-1G>T. Disruption of this splice site has been observed in individual(s) with pyridoxine dependent epilepsy (PMID: 17068770, 23350806). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs140845195, gnomAD 0.004%). (less)
Pathogenic (Sep 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pyridoxine-dependent epilepsy caused by ALDH7A1 mutant (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812340.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (4) PubMed: 17068770‚ 23350806‚ 30043187‚ 31990480 Comment: This sequence change in ALDH7A1 occurs within the canonical splice acceptor site of intron 17. It is predicted to cause the activation of the cryptic … (more) This sequence change in ALDH7A1 occurs within the canonical splice acceptor site of intron 17. It is predicted to cause the activation of the cryptic splice site in exon 18 leading to an in-frame five amino acid deletion (removes amino acids 495-499) which has been confirmed by RT-PCR on patient lymphoblast cells (PMID: 23350806). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.004% (4/113,332 alleles) in the European (non-Finnish) population. This variant has been detected in multiple individuals with pyridoxine-dependent epilepsy, homozygous and compound heterozygous with a second pathogenic variant (PMID: 23350806, 17068770, 31990480, 30043187). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Moderate, PM3_VeryStrong, PM2_Supporting (less)
Pathogenic (Jan 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002497344.19 First in ClinVar: Apr 08, 2022 Last updated: Dec 22, 2024	Number of individuals with the variant: 1
Pathogenic (Jan 02, 2024)	no assertion criteria provided Method: clinical testing	ALDH7A1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004724807.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The ALDH7A1 c.1566-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in individuals … (more) The ALDH7A1 c.1566-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in individuals with pyridoxine-dependent epilepsy (Plecko et al. 2007. PubMed ID: 17068770; Pérez et al. 2013. PubMed ID: 23350806; Coughlin et al. 2019. PubMed ID: 30043187. Table S2). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in ALDH7A1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

Comment:

Observed in the homozygous state, with a pathogenic variant on the opposite allele (in trans), or with a second ALDH7A1 variant, phase unknown, in individuals with pyridoxine-dependent epilepsy in the published literature and not observed in homozygous state in controls (PMID: 30043187, 17068770); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Previously reported as c.1482-1 G>T due to alternative nomenclature; This variant is associated with the following publications: (PMID: 31589614, 29286531, 31990480, 17068770, 36011376, 30043187, 31440721, 31623504)

Comment:

This sequence change affects an acceptor splice site in intron 17 of the ALDH7A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 5 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 18 (PMID: 23350806). ClinVar contains an entry for this variant (Variation ID: 374140). This variant is also known as c.1482-1G>T. Disruption of this splice site has been observed in individual(s) with pyridoxine dependent epilepsy (PMID: 17068770, 23350806). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs140845195, gnomAD 0.004%).

Comment:

This sequence change in ALDH7A1 occurs within the canonical splice acceptor site of intron 17. It is predicted to cause the activation of the cryptic splice site in exon 18 leading to an in-frame five amino acid deletion (removes amino acids 495-499) which has been confirmed by RT-PCR on patient lymphoblast cells (PMID: 23350806). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.004% (4/113,332 alleles) in the European (non-Finnish) population. This variant has been detected in multiple individuals with pyridoxine-dependent epilepsy, homozygous and compound heterozygous with a second pathogenic variant (PMID: 23350806, 17068770, 31990480, 30043187). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Moderate, PM3_VeryStrong, PM2_Supporting

Comment:

The ALDH7A1 c.1566-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in individuals with pyridoxine-dependent epilepsy (Plecko et al. 2007. PubMed ID: 17068770; Pérez et al. 2013. PubMed ID: 23350806; Coughlin et al. 2019. PubMed ID: 30043187. Table S2). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in ALDH7A1 are expected to be pathogenic. This variant is interpreted 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The case of pyridoxine dependent epilepsy misdiagnosed as non-ketotic hyperglycinemia.	Gazeteci-Tekin H	The Turkish journal of pediatrics	2019	PMID: 31990480
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
Clinical, biochemical, and molecular studies in pyridoxine-dependent epilepsy. Antisense therapy as possible new therapeutic option.	Pérez B	Epilepsia	2013	PMID: 23350806
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene.	Plecko B	Human mutation	2007	PMID: 17068770
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs140845195 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_001182.5(ALDH7A1):c.1566-1G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs140845195 ...