NM_001182.5(ALDH7A1):c.1547A>G (p.Tyr516Cys) AND Pyridoxine-dependent epilepsy

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV000802615.12

Allele description

NM_001182.5(ALDH7A1):c.1547A>G (p.Tyr516Cys)

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.1547A>G (p.Tyr516Cys)

HGVS:

NC_000005.10:g.126546342T>C
NG_008600.2:g.54049A>G
NM_001182.5:c.1547A>GMANE SELECT
NM_001201377.2:c.1463A>G
NM_001202404.2:c.1355A>G
NP_001173.2:p.Tyr516Cys
NP_001188306.1:p.Tyr488Cys
NP_001189333.2:p.Tyr452Cys
NC_000005.9:g.125882034T>C
NM_001182.4:c.1547A>G

Protein change:

Y452C

Links:

dbSNP: rs200102503

NCBI 1000 Genomes Browser:

rs200102503

Molecular consequence:

NM_001182.5:c.1547A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001201377.2:c.1463A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001202404.2:c.1355A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Pyridoxine-dependent epilepsy (EPEO4)
Synonyms:: Pyridoxine dependency; Pyridoxine dependency with seizures; Vitamin B6-dependent seizures; 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
SCV000942454	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29852413, 31737911, 31965297, 28492532
SCV002024329	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 28, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002570075	Center of Excellence for Medical Genomics, Chulalongkorn University	no assertion criteria provided	Likely pathogenic (Sep 8, 2002)	paternal	research
SCV004050017	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 11, 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	paternal	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Diagnostic yield of targeted massively parallel sequencing in children with epileptic encephalopathy.

Kothur K, Holman K, Farnsworth E, Ho G, Lorentzos M, Troedson C, Gupta S, Webster R, Procopis PG, Menezes MP, Antony J, Ardern-Holmes S, Dale RC, Christodoulou J, Gill D, Bennetts B.

Seizure. 2018 Jul;59:132-140. doi: 10.1016/j.seizure.2018.05.005. Epub 2018 May 28.

PubMed [citation]

PMID:: 29852413

Clinical and genetic features in pyridoxine-dependent epilepsy: a Chinese cohort study.

Jiao X, Xue J, Gong P, Wu Y, Zhang Y, Jiang Y, Yang Z.

Dev Med Child Neurol. 2020 Mar;62(3):315-321. doi: 10.1111/dmcn.14385. Epub 2019 Nov 18.

PubMed [citation]

PMID:: 31737911

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000942454.4

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

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 516 of the ALDH7A1 protein (p.Tyr516Cys). This variant is present in population databases (rs200102503, gnomAD 0.1%). This missense change has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 29852413, 31737911, 31965297). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 647989). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALDH7A1 protein function with a positive predictive value of 95%. 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 Revvity Omics, Revvity, SCV002024329.3

#	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 Center of Excellence for Medical Genomics, Chulalongkorn University, SCV002570075.1

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

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

From Genome-Nilou Lab, SCV004050017.1

#	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

Last Updated: Mar 16, 2024

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