NM_139058.3(ARX):c.1444G>A (p.Gly482Ser) AND Developmental and epileptic encephalopathy, 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 9, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001003472.5

Allele description [Variation Report for NM_139058.3(ARX):c.1444G>A (p.Gly482Ser)]

NM_139058.3(ARX):c.1444G>A (p.Gly482Ser)

Gene:

ARX:aristaless related homeobox [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp21.3

Genomic location:

Preferred name:

NM_139058.3(ARX):c.1444G>A (p.Gly482Ser)

HGVS:

NC_000023.11:g.25007115C>T
NG_008281.1:g.13834G>A
NM_139058.3:c.1444G>AMANE SELECT
NP_620689.1:p.Gly482Ser
NC_000023.10:g.25025232C>T
NM_139058.2:c.1444G>A

Protein change:

G482S

Links:

dbSNP: rs1468724042

NCBI 1000 Genomes Browser:

rs1468724042

Molecular consequence:

NM_139058.3:c.1444G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Developmental and epileptic encephalopathy, 1 (DEE1)
Synonyms:: INFANTILE SPASM SYNDROME, X-LINKED 1; X-linked infantile spasms; West's syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010632; MedGen: C3463992; OMIM: 308350

Recent activity

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Mus musculus serine (or cysteine) peptidase inhibitor, clade A (alpha-1 antiprot...
Mus musculus serine (or cysteine) peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 10 (Serpina10), transcript variant 1, mRNA
gi|2319699971|ref|NM_144834.5|

Nucleotide
Homo sapiens guanylate cyclase activator 1B (GUCA1B), RefSeqGene on chromosome 6
Homo sapiens guanylate cyclase activator 1B (GUCA1B), RefSeqGene on chromosome 6
gi|2296125237|ref|NG_016216.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001161761	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 9, 2017)	de novo	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17668384, 20300201, 16523516, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001161761

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 9, 2017)

de novo

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome).

Kato M, Saitoh S, Kamei A, Shiraishi H, Ueda Y, Akasaka M, Tohyama J, Akasaka N, Hayasaka K.

Am J Hum Genet. 2007 Aug;81(2):361-6. Epub 2007 Jun 11.

PubMed [citation]

PMID:: 17668384
PMCID:: PMC1950814

Mutations in ARX Result in Several Defects Involving GABAergic Neurons.

Friocourt G, Parnavelas JG.

Front Cell Neurosci. 2010;4:4. doi: 10.3389/fncel.2010.00004.

PubMed [citation]

PMID:: 20300201
PMCID:: PMC2841486

See all PubMed Citations (4)

Details of each submission

From Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital, SCV001161761.1

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

Description

[ACMG/AMP: PS2, PM2, PP2, PP3]; A de novo mosaic variant [PS2] within the ARX gene was detected and confirmed by sanger sequencing. This alteration results in the replacement of a glycine residue with a serine at amino acid 482 (p.Gly482Ser), and occurs at a position which is evolutionarily conserved and predicated to have a deleterious effect based on in silico modeling [PP3]. Notably, a single hemizygous allele with the p.Gly482Ser variant has been reported in the gnomAD population database among approximately 140,000 total alleles at that position [PM2]. The spectrum of disease associated variation within ARX is broad, and includes polyalanine expansion, truncating alterations, insertion deletion events and missense changes (PMID: 17668384; 20300201). Missense variants are a common mechanism of disease in this gene and the rate of benign missense variants is low [PP2]. Mosaicism has been previously documented in ARX (PMID: 16523516).

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

Last Updated: Aug 5, 2023

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