rs121912707

Variant names:

• chr5-126552059-C-G
• rs121912707
• NM_001182.5:c.1279G>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP2 PP3 PP5_Very_Strong

The NM_001182.5(ALDH7A1):​c.1279G>C​(p.Glu427Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E427G) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35 O:1
• Conservation: PhyloP100: 7.79
• Publications: 50 publications found

Genes affected

ALDH7A1 (HGNC:877): (aldehyde dehydrogenase 7 family member A1) The protein encoded by this gene is a member of subfamily 7 in the aldehyde dehydrogenase gene family. These enzymes are thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. This particular member has homology to a previously described protein from the green garden pea, the 26g pea turgor protein. It is also involved in lysine catabolism that is known to occur in the mitochondrial matrix. Recent reports show that this protein is found both in the cytosol and the mitochondria, and the two forms likely arise from the use of alternative translation initiation sites. An additional variant encoding a different isoform has also been found for this gene. Mutations in this gene are associated with pyridoxine-dependent epilepsy. Several related pseudogenes have also been identified. [provided by RefSeq, Jan 2011]

ALDH7A1 Gene-Disease associations (from GenCC):

• pyridoxine-dependent epilepsy

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet, ClinGen
• pyridoxine-dependent epilepsy caused by ALDH7A1 mutant

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_001182.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-126552058-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 944165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 0.36846 (below the threshold of 3.09). Trascript score misZ: 0.93117 (below the threshold of 3.09). GenCC associations: The gene is linked to pyridoxine-dependent epilepsy, pyridoxine-dependent epilepsy caused by ALDH7A1 mutant.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78
• PP5: Variant 5-126552059-C-G is Pathogenic according to our data. Variant chr5-126552059-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.1279G>C	p.Glu427Gln	missense_variant	Exon 14 of 18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2	c.1195G>C	p.Glu399Gln	missense_variant	Exon 14 of 18		NP_001188306.1
ALDH7A1	NM_001202404.2	c.1087G>C	p.Glu363Gln	missense_variant	Exon 12 of 16		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.1279G>C	p.Glu427Gln	missense_variant	Exon 14 of 18	1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000358 AC: 90 AN: 251230 AF XY: 0.000361

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000543 AC: 793 AN: 1461696 Hom.: 0 Cov.: 32 AF XY: 0.000532 AC XY: 387 AN XY: 727150

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5676

European-Non Finnish (NFE) AF: 0.000673 AC: 748 AN: 1111968

Other (OTH) AF: 0.000431 AC: 26 AN: 60376

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74464

African (AFR) AF: 0.000120 AC: 5 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000499 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:35 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyridoxine-dependent epilepsy Pathogenic:26 Other:1

Mar 30, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 18, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 25, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 α-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.

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 20, 2015

Courtagen Diagnostics Laboratory, Courtagen Life Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 01, 2023

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 06, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 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 (>=0.6, sensitivity 0.72 and precision 0.9)]. 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.

Nov 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Sep 23, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 18, 2021

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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

Dec 07, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 08, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 13, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PM5_STR,PP3

Aug 26, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 02, 2017

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 05, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jun 18, 2013

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 12, 2020

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:6

Feb 23, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 03, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate the variant abolishes enzyme activity (Mills et al., 2006; Coulter-Mackie et al., 2012); 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: 31652343, 16491085, 26555630, 17068770, 17088338, 17721876, 26224730, 29056246, 31164858, 31980526, 20370816, 22371912, 22784480, 27438048, 26995068, 26943461, 16159904, 28832562, 29453417, 30609409, 29401530, 31737911, 31564432, 23430810, 30043187, 31130284, 23022070, 31589614, 34426522, 32685344)

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 28, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALDH7A1: PM3:Very Strong, PM1, PM2, PM5, PP3, PS3:Supporting

Seizure Pathogenic:2

Sep 23, 2024

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 13, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E427Q pathogenic mutation (also known as c.1279G>C), located in coding exon 14 of the ALDH7A1 gene, results from a G to C substitution at nucleotide position 1279. The glutamic acid at codon 427 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been described in numerous unrelated individuals with pyroxidine-dependent seizures in both homozygous and compound heterozygous states, and is reported to be the most common ALDH7A1 mutation, accounting for approximately 30% of mutant alleles (Mills PB et al. Nat. Med., 2006 Mar;12:307-9; Plecko B et al. Hum. Mutat., 2007 Jan;28:19-26; Bennett CL et al. Epilepsia, 2009 May;50:1167-75; Nam SH et al. Ann. Clin. Lab. Sci., 2012;42:65-72; Mefford HC et al. Neurology, 2015 Sep;85:756-62; Butler KM et al.<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px"> Pediatr. Neurol.<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px">, 2017 Dec;77:61-66<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px">). Enzyme activity in transfected CHO cells and E. coli cells have demonstrated undetectable or extremely low (<3% of WT) enzyme activity (Mills PB et al. Nat. Med., 2006 Mar;12:307-9; Coulter-Mackie MB et al. Mol. Genet. Metab., 2012 Aug;106:478-81). <span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px">In addition, this alteration is predicted to be probably damaging, deleterious, and deleterious by PolyPhen and<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px"> SIFT<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px"> in silico<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px"> analyses, respectively.Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Pyridoxine-dependent epilepsy caused by ALDH7A1 mutant Pathogenic:1

May 04, 2022

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The homozygous p.Glu427Gln variant in ALDH7A1 was identified by our study in 1 individual with pyridoxine-dependent epilepsy. The variant has been reported in at least 10 individuals of European and unknown ethnicity with pyridoxine-dependent epilepsy (PMID: 16491085, 19128417), and has been identified in 0.06% (79/129032) of European non-Finnish, 0.02% (4/19918) of East Asian, and 0.01% (4/35418) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121912707). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 17994) as pathogenic by multiple submitters and as likely pathogenic by UCLA Clinical Genomics Center. In vitro functional studies provide some evidence that the p.Glu427Gln variant may impact protein function (PMID: 22784480, 16491085). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in at least 5 affected homozygotes, and in combination with 2 reported pathogenic variants, and in at least 10 individuals with pyridoxine-dependent epilepsy increases the likelihood that the p.Glu427Gln variant is pathogenic (VariationID: 17995, 204852; PMID: 16491085, 19128417). The p.Glu427Gln variant is located in a region of ALDH7A1 that is essential to protein folding and stability, suggesting that this variant is in a mutational hotspot and slightly supports pathogenicity (PMID: 16491085, 31652343). One additional likely pathogenic variants, resulting in a different amino acid change at the same position (p.Glu427Gly), have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 19128417). In summary, the p.Glu427Gln variant is pathogenic based off of our findings of multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM3_strong, PM5_supporting, PM1, PS3_moderate, PP3 (Richards 2015).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;D;T;.;T;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.0	.;H;.;.;.;.;.;.
PhyloP100		7.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.0	.;D;.;.;.;.;.;D
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	.;D;.;.;.;.;.;D
Vest4		0.0
ClinPred		0.35	T
GERP RS		4.9
Varity_R		0.93
gMVP		0.97
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121912707; hg19: chr5-125887751;