NM_001182.5(ALDH7A1):c.1279G>C (p.Glu427Gln) AND Pyridoxine-dependent epilepsy

Germline classification:: Pathogenic/Likely pathogenic (28 submissions)
Last evaluated:: Feb 3, 2026
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000019610.87

Allele description [Variation Report for NM_001182.5(ALDH7A1):c.1279G>C (p.Glu427Gln)]

NM_001182.5(ALDH7A1):c.1279G>C (p.Glu427Gln)

Gene:

ALDH7A1:aldehyde dehydrogenase 7 family member A1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q23.2

Genomic location:

Preferred name:

NM_001182.5(ALDH7A1):c.1279G>C (p.Glu427Gln)

Other names:

p.E427Q:GAG>CAG; NM_001182.5(ALDH7A1):c.1279G>C

HGVS:

NC_000005.10:g.126552059C>G
NG_008600.3:g.48332G>C
NM_001182.5:c.1279G>CMANE SELECT
NM_001201377.2:c.1195G>C
NM_001202404.2:c.1087G>C
NP_001173.2:p.Glu427Gln
NP_001188306.1:p.Glu399Gln
NP_001189333.2:p.Glu363Gln
NC_000005.9:g.125887751C>G
NG_008600.2:g.48332G>C
NM_001182.3:c.1279G>C
NM_001182.4:c.1279G>C
NM_001201377.1:c.1195G>C
P49419:p.Glu427Gln

Protein change:

E363Q; GLU399GLN

Links:

UniProtKB: P49419#VAR_031719; OMIM: 107323.0001; dbSNP: rs121912707

Molecular consequence:

NM_001182.5:c.1279G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001201377.2:c.1195G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001202404.2:c.1087G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Pyridoxine-dependent epilepsy (EPEO4)
Synonyms:: PYRIDOXINE DEPENDENCY WITH SEIZURES; Pyridoxine-Dependent Epilepsy - ALDH7A1; EPILEPSY, EARLY-ONSET, 4, VITAMIN B6-DEPENDENT; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009945; MedGen: C1849508; Orphanet: 3006; OMIM: 266100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039908	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2007)	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 16491085, 17068770, 17721876, 16159904, 17088338
SCV000236511	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	criteria provided, single submitter (Courtagen Life Sciences Classifications)	Pathogenic (Feb 20, 2015)	germline	clinical testing	Citation Link,
SCV000255323	UCLA Clinical Genomics Center, UCLA - CES	criteria provided, single submitter (Lee et al. (JAMA. 2014))	Likely pathogenic (Jun 18, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000551314	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 3, 2026)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19128417, 22371912, 26224730, 16491085, 28492532
SCV000611247	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000711784	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 26, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22371912, 23022070, 23430810, 16491085, 20370816, 22784480, 25741868
SCV000743970	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Oct 8, 2014)	germline	clinical testing	Citation Link,
SCV000745919	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided (ACGS Guidelines, 2013)	Pathogenic (Jan 18, 2017)	germline	clinical testing	Citation Link,
SCV000916081	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Aug 25, 2017)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 26224730, 23430810, 22784480, 22371912, 20370816, 19128417, 16491085, 23054014 Citation Link,
SCV000996079	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 2, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001424279	Elsea Laboratory, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 1, 2020)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001775553	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 30043187, 20301659
SCV001994763	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 18, 2021)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002059141	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 2025)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22784480, 19128417, 16491085, 25741868
SCV002098022	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Jun 12, 2020)	germline	clinical testing	Citation Link,
SCV002318362	Génétique des Maladies du Développement, Hospices Civils de Lyon	no assertion criteria provided	Likely pathogenic	maternal	clinical testing
SCV002495769	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002558976	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002581883	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 23, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002759308	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 7, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002768339	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30043187, 25741868
SCV003927895	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	no assertion criteria provided	Pathogenic (Apr 1, 2023)	germline	clinical testing
SCV004050590	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004564843	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 14, 2023)	germline	clinical testing	Citation Link,
SCV004698048	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 13, 2024)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004805159	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 17, 2024)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV006086136	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 5, 2025)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22784480, 17068770, 16491085 Citation Link,
SCV007540794	Department of Human Genetics, Hannover Medical School	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing, literature only, research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

An intriguing "silent" mutation and a founder effect in antiquitin (ALDH7A1).

Salomons GS, Bok LA, Struys EA, Pope LL, Darmin PS, Mills PB, Clayton PT, Willemsen MA, Jakobs C.

Ann Neurol. 2007 Oct;62(4):414-8.

PubMed [citation]

PMID:: 17721876

Epidemiology of pyridoxine dependent seizures in the Netherlands.

Been JV, Bok LA, Andriessen P, Renier WO.

Arch Dis Child. 2005 Dec;90(12):1293-6. Epub 2005 Sep 13.

PubMed [citation]

PMID:: 16159904
PMCID:: PMC1720231

See all PubMed Citations (18)

Details of each submission

From OMIM, SCV000039908.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

Description

In an Austrian child with early-onset vitamin B6-dependent epilepsy-4 (EPEO4; 266100), Mills et al. (2006) identified a homozygous 1195G-C transversion in exon 14 of the ALDH7A1 gene, resulting in a glu399-to-gln (E399Q) substitution. Another affected child of Dutch descent was compound heterozygous for E399Q and R82X (107323.0002). In vitro functional expression studies in Chinese hamster ovary cells showed that the mutant enzyme had no detectable activity.

In a study by Plecko et al. (2007) involving 18 patients with neonatal seizure onset, the E399Q mutation accounted for 12 of 36 alleles.

Salomons et al. (2007) identified a homozygous E399Q mutation in 7 Dutch patients from 4 apparently unrelated families with pyridoxine-dependent epilepsy. The patients had previously been reported by Been et al. (2005) and Bok et al. (2007).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Courtagen Diagnostics Laboratory, Courtagen Life Sciences, SCV000236511.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From UCLA Clinical Genomics Center, UCLA - CES, SCV000255323.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000551314.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 427 of the ALDH7A1 protein (p.Glu427Gln). This variant is present in population databases (rs121912707, gnomAD 0.06%). This missense change has been observed in individual(s) with pyridoxine dependent epilepsy (PMID: 16491085, 19128417, 22371912, 26224730). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17994). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 16491085). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000611247.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711784.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.Glu427Gln variant in ALDH7A1 (also referred to as p.Glu399Gln in the literature) has been reported in at least 3 homozygous and 7 compound heterozygous individuals with pyridoxine-dependent epilepsy (Mills 2006 PMID: 16491085, Schmitt 2010 PMID: 20370816, Nam 2012 PMID: 22371912, Proudfoot 2012 PMID: 23430810, van Karnebeek 201 PMID: 230220702). This variant has also been identified in 45/66588 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121912707). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In addition, in vitro functional studies provide evidence that the p.Glu427Gln variant impacts protein function (Mills 2006 PMID: 16491085, Coulter-Mackie 2012 PMID: 22784480). In summary, this variant meets our criteria to be classified as pathogenic for pyridoxine-dependent epilepsy in an autosomal recessive manner based upon its co-occurrence with pathogenic variants in affected individuals and functional evidence. ACMG/AMP criteria applied: PM3_VeryStrong, PS3, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV000743970.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV000745919.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000916081.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Across a selection of available literature, the ALDH7A1 c.1279G>C (p.Glu427Gln) missense variant, also referred to as p.Glu399Gln, has been reported in at least seven studies and identified in a total of 15 individuals, including in six in a homozygous state and in nine in a compound heterozygous state, all of whom have a diagnosis of pyridoxine-dependent epilepsy or seizures (Mills et al. 2006; Bennett et al. 2009; Schmitt et al. 2010; Nam et al. 2012; Proudfoot et al. 2013; Tlili et al. 2013; Mefford et al. 2015). The p.Glu427Gln variant was absent from 230 controls but is reported at a frequency of 0.00081 in the European American population of the Exome Sequencing Project. Functional studies using transfected CHO cells were performed by Mills et al. (2006) and found Î±-AASA dehydrogenase activity to be undetectable. Coulter-Mackie et al. (2012) used transfected E. coli and observed enzyme activity levels below the level of detection for the assay. Based on the collective evidence, the p.Glu427Gln variant is classified as pathogenic for pyridoxine-dependent epilepsy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000996079.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The p.Glu427Gln (commonly referred to in the literature as p.Glu399Gln) is missense variant in the ALDH7A1 gene. This variant is well reported in the literature, and had been reported to be the most prevalent pathogenic variant in ALDH7A1 (PMID: 20301659). The variant has been reported by multiple clinical laboratories as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/RCV000019610.29/). Functional studies have shown that the p.Glu427Gln results in an absence of detectable enzyme activity in a CHO in vitro cell model (PMID: 16491085). The highest reported allele frequency in the population databases is 0.0006% (81/126556 alleles). In silico modeling predicts this variant as damaging and it is highly conserved. Based on the available evidence, the p.Glu427Gln variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Elsea Laboratory, Baylor College of Medicine, SCV001424279.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV001775553.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

The most common pathogenic variant, accounting for 33% of pathogenic variants

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV001994763.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002059141.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.051%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 16491085, 22784480). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.97 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017994 /PMID: 16491085 /3billion dataset). Different missense changes at the same codon (p.Glu427Asp, p.Glu427Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000204865, VCV000944165 /PMID: 19128417). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From New York Genome Center - CSER-NYCKidSeq, SCV002098022.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Génétique des Maladies du Développement, Hospices Civils de Lyon, SCV002318362.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV002495769.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

ALDH7A1 NM_001182.4 exon 14 p.Glu427Gln (c.1279G>C): This variant is a well known pathogenic variant and has been reported in the literature in numerous individuals with pyridoxine dependent epilepsy in the homozygous and compound heterozygous state (also reported as p.Glu399Gln; selected publications: Mills 2006 PMID:16491085, Bennett 2009 PMID:19128417, Schmitt 2010 PMID:20370816, van Karnebeek 2012 PMID:23022070, Mefford 2015 PMID:26224730, Coughlin 2019 PMID:30043187). Multiple publications suggest that this variant represents 1/3rd of mutated alleles for this gene (Bennett 2009 PMID:19128417, Mefford 2015 PMID:26224730). This variant is present in 0.04% (29/68034) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-126552059-C-G?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic (Variation ID:17994). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies utilizing chinese hamster ovary cells and e.coli assays have shown a deleterious effect of this variant (Mills 2006 PMID:16491085, Coulter-Mackie 2012 PMID:22784480). Furthermore, other variants at this position (p.Glu427Gly/p.Glu399Gly and p.Glu427Asp/p.Glu399Gly) have also been reported in association with disease supporting that this codon has functional importance. In summary, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille, SCV002558976.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002581883.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV002759308.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768339.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pyridoxine-dependent epilepsy (MIM#266100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (93 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated NAD binding site within the aldehyde dehydrogenase domain (NCBI, DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and is described as the most common pathogenic variant among European patients (ClinVar, PMID: 30043187). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), SCV003927895.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV004050590.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004564843.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The ALDH7A1 c.1279G>C; p.Glu427Gln variant (rs121912707), also known as Glu399Gln for legacy nomenclature, is reported as a common pathogenic variant that has been identified both homozygous and compound heterozygous in several individuals with autosomal recessive epilepsy (Bennett 2009, Mefford 2015, Monies 2019, Schmitt 2010). Additionally, other variants at this codon (p.Glu427Asp, p.Glu427Gly) have also been reported in affected individuals (Bennett 2009). The p.Glu427Gln variant is reported in ClinVar (Variation ID: 17994). It is observed in the general population with an overall allele frequency of 0.03% (93/282634 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.944). In support of these predictions, functional analyses show an effect of this variant on enzyme activity (Coulter-Mackie 2012). Based on available information, this variant is considered to be pathogenic. References: Bennett CL et al. Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients. Epilepsia. 2009 May;50(5):1167-75. PMID: 19128417. Coulter-Mackie MB et al. Overexpression of human antiquitin in E. coli: enzymatic characterization of twelve ALDH7A1 missense mutations associated with pyridoxine-dependent epilepsy. Mol Genet Metab. 2012 Aug;106(4):478-81. PMID: 22784480. Mefford HC et al. Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination. Neurology. 2015 Sep 1;85(9):756-62. PMID: 26224730. Monies D et al. Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Am J Hum Genet. 2019 Jun 6;104(6):1182-1201. PMID: 31130284. Schmitt B et al. Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency. Dev Med Child Neurol. 2010 Jul;52(7):e133-42. PMID: 20370816.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004698048.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Criteria applied: PM3_VSTR,PM5_STR,PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV004805159.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV006086136.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: ALDH7A1 c.1279G>C (p.Glu427Gln) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00036 in 251230 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ALDH7A1 causing Pyridoxine-Dependent Epilepsy (0.00036 vs 0.0018), allowing no conclusion about variant significance. The variant, Glu427Gln (aka Glu399Gln), has been observed in several homozygous- and compound heterozygous individuals affected with Pyridoxine-Dependent Epilepsy (e.g. Mills_2006, Plecko_2007). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1281G>T, p.Glu427Asp), supporting the critical relevance of codon 427 to ALDH7A1 protein function. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated undetectable activity for the variant protein (e.g. Mills_2006, Coulter-Mackie_2012). The following publications have been ascertained in the context of this evaluation (PMID: 16491085, 17068770, 22784480). ClinVar contains an entry for this variant (Variation ID: 17994). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Human Genetics, Hannover Medical School, SCV007540794.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 27, 2026

Relating variation to medicine