ClinVar Miner

Submissions for variant NM_001182.5(ALDH7A1):c.1279G>C (p.Glu427Gln) (rs121912707)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000718443 SCV000849306 pathogenic Seizures 2018-03-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 2 of classification of c (below) met (2c = 1b),Other strong data supporting pathogenic classification ,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000186744 SCV000610621 pathogenic not provided 2017-06-28 criteria provided, single submitter clinical testing
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000019610 SCV000236511 pathogenic Pyridoxine-dependent epilepsy 2015-02-20 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000186744 SCV000226071 pathogenic not provided 2015-02-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000019610 SCV000611247 pathogenic Pyridoxine-dependent epilepsy 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000186744 SCV000240311 pathogenic not provided 2018-12-28 criteria provided, single submitter clinical testing The E427Q pathogenic variant in the ALDH7A1 gene has been identified (using alternative nomenclature of E399Q) in multiple unrelated patients with pyridoxine-dependent epilepsy who had a second ALDH7A1 pathogenic variant on the other chromosome (Mills et al., 2006; Schmitt et al., 2010). This variant is observed in 45/66588 (0.07%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E427Q variant is a semi-conservative amino acid substitution that alters a highly conserved position in the ALDH7A1 protein, and functional studies indicate that it abolishes enzyme activity (Mills et al., 2006; Coulter-Mackie et al., 2012). We interpret E427Q as a pathogenic variant.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000019610 SCV000743970 pathogenic Pyridoxine-dependent epilepsy 2014-10-08 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000019610 SCV000745919 pathogenic Pyridoxine-dependent epilepsy 2017-01-18 no assertion criteria provided clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000019610 SCV000916081 pathogenic Pyridoxine-dependent epilepsy 2017-08-25 criteria provided, single submitter 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.
Invitae RCV000019610 SCV000551314 pathogenic Pyridoxine-dependent epilepsy 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 427 of the ALDH7A1 protein (p.Glu427Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs121912707, ExAC 0.07%). This variant has been reported in multiple individuals affected with pyridoxine dependent epilepsy (PMID: 16491085, 19128417, 26224730, 22371912), including a family in which it segregated with disease in two affected children (PMID: 19128417, 26224730). This variant is also known in the literature as Glu399Gln. ClinVar contains an entry for this variant (Variation ID: 17994). Experimental studies have shown that this missense change, when expressed in CHO cells, resulted in no detectable enzyme activity (PMID: 16491085), indicating that this missense variant completely abolishes protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000019610 SCV000711784 pathogenic Pyridoxine-dependent epilepsy 2016-03-02 criteria provided, single submitter clinical testing The p.Glu427Gln variant in ALDH7A1 (also referred to as p.Glu399Gln in the liter ature) has been reported in at least 3 homozygous and 7 compound heterozygous in dividuals with pyridoxine-dependent epilepsy (Mills 2006, Schmitt 2010, Nam 2012 , Proudfoot 2012, van Karnebeek 2012). This variant has also been identified in 45/66588 of European chromosomes by the Exome Aggregation Consortium (ExAC, http ://; dbSNP rs121912707). Although this variant has been s een 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, Cou lter-Mackie 2012). 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 a nd functional evidence.
OMIM RCV000019610 SCV000039908 pathogenic Pyridoxine-dependent epilepsy 2007-10-01 no assertion criteria provided literature only
UCLA Clinical Genomics Center, UCLA RCV000019610 SCV000255323 likely pathogenic Pyridoxine-dependent epilepsy 2013-06-18 criteria provided, single submitter clinical testing

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