NM_001182.4(ALDH7A1):c.1279G>C (p.Glu427Gln) AND Pyridoxine-dependent epilepsy

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Pathogenic(4) (Last evaluated: Nov 25, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000019610.29

Allele description [Variation Report for NM_001182.4(ALDH7A1):c.1279G>C (p.Glu427Gln)]

NM_001182.4(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_001182.4(ALDH7A1):c.1279G>C (p.Glu427Gln)
Other names:
p.E427Q:GAG>CAG
HGVS:
  • NC_000005.10:g.126552059C>G
  • NG_008600.2:g.48332G>C
  • NM_001182.4:c.1279G>C
  • NM_001201377.1:c.1195G>C
  • NP_001173.2:p.Glu427Gln
  • NP_001188306.1:p.Glu399Gln
  • NC_000005.9:g.125887751C>G
  • NM_001182.3:c.1279G>C
  • NP_001189333.1:p.Glu390Gln
  • P49419:p.Glu427Gln
Protein change:
E363Q; GLU399GLN
Links:
UniProtKB: P49419#VAR_031719; OMIM: 107323.0001; dbSNP: 121912707
GMAF:
0.0002(G), 121912707
NCBI 1000 Genomes Browser:
rs121912707
Allele Frequency:
NaN, GO-ESP
Molecular consequence:
  • NM_001182.4:c.1279G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Pyridoxine-dependent epilepsy (EPD)
Synonyms:
Pyridoxine-Dependent Seizures
Identifiers:
MedGen: C1849508; Orphanet: 3006; OMIM: 266100
Age of onset:
Antenatal
Prevalence:
1-9 / 1 000 000 3006

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000039908OMIMno assertion criteria providedPathogenic
(Oct 1, 2007)
germlineliterature only

PubMed (5)
[See all records that cite these PMIDs]

SCV000226071EGL Genetic Diagnostics,Eurofins Clinical Diagnosticscriteria provided, single submitter
Pathogenic
(Feb 23, 2015)
germlineclinical testing

Citation Link,

SCV000236511Courtagen Diagnostics Laboratory,Courtagen Life Sciencescriteria provided, single submitter
Pathogenic
(Feb 20, 2015)
germlineclinical testing

Citation Link,

SCV000255323UCLA Clinical Genomics Center, UCLA - CEScriteria provided, single submitter
Likely pathogenic
(Jun 18, 2013)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000551314Invitaecriteria provided, single submitter
Pathogenic
(Nov 25, 2016)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown1not providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Mutations in antiquitin in individuals with pyridoxine-dependent seizures.

Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen MA, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT.

Nat Med. 2006 Mar;12(3):307-9. Epub 2006 Feb 19.

PubMed [citation]
PMID:
16491085

Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene.

Plecko B, Paul K, Paschke E, Stoeckler-Ipsiroglu S, Struys E, Jakobs C, Hartmann H, Luecke T, di Capua M, Korenke C, Hikel C, Reutershahn E, Freilinger M, Baumeister F, Bosch F, Erwa W.

Hum Mutat. 2007 Jan;28(1):19-26.

PubMed [citation]
PMID:
17068770
See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000039908.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (5)

Description

In an Austrian child with pyridoxine-dependent epilepsy (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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, SCV000226071.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From UCLA Clinical Genomics Center, UCLA - CES, SCV000255323.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000551314.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 30, 2017