Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ALDH7A1 : pyridoxine-dependent epilepsy

HGNC:877 | MONDO_0009945
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 8
Mills PB et al. 2006 Mar (PMID:16491085); Salomons GS et al. 2007 Oct (PMID:17721876);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
Mills PB et al. 2006 Mar (PMID:16491085);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
Mills PB et al. 2006 Mar (PMID:16491085);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Jansen LA et al. 2014 Jan (PMID:24122892);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1 0.5
Coulter-Mackie MB et al. 2012 Aug (PMID:22784480);
Models Non-human model organism 2 0 - 4 4 2 6 4
Pena IA et al. 2017 Dec (PMID:29061647); Zabinyakov N et al. 2017 Oct 20 (PMID:29053735);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between ALDH7A1 and pyridoxine-dependent epilepsy (PDE) was evaluated using the ClinGen Clinical Validity Framework as of June 28th, 2019. Patients with this same condition have also been reported as having folinic acid responsive seizures (Gallagher et al, 2009, PMID 19142996). ALDH7A1 encodes alpha-aminoadipic acid semialdehyde dehydrogenase, also known as antiquitin, which converts alpha-aminoadipic acid semialdehyde (AASA) to alpha-aminoadipic acid, a critical step in lysine catabolism. Variants in ALDH7A1 causing PDE were first reported by Mills et al, 2006 (PMID 16491085). Since then, over eighty PDE-associated variants have been reported in ALDH7A1 (see Pena et al, 2017, PMID 30058881, for review). Data from 10 patients with 9 unique variants (missense, nonsense, frameshift, and splicing) from 2 publications were curated (Mills et al, 2006, PMID 16491085; Salomons et al, 2007, PMID 17721876). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by the biochemical function of alpha-aminoadipic acid semialdehyde dehydrogenase (antiquitin), which is consistent with the biochemical and clinical features of the disease (Mills et al, 2006, PMID 16491085), expression in brain (Jansen et al, 2014; PMID 24122892), functional studies of missense variants (Coulter-Mackie et al, 2012, PMID 22784480), and the phenotype observed in two CRISPR-generated aldh7a1 zebrafish models (Pena et al, 2017; PMID 29061647; Zabinyakov et al, 2017, PMID 29053735). Additional experimental data supporting the gene-disease relationship is available but the maximum score for experimental evidence (6 points) has been reached. Data curated by Illumina is included in this curation. In summary, ALDH7A1 is definitively associated with autosomal recessive PDE. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on July 26, 2019.