NM_139058.3(ARX):c.1150C>T (p.Arg384Cys) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 22, 2022
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:: RCV003072879.3

Allele description [Variation Report for NM_139058.3(ARX):c.1150C>T (p.Arg384Cys)]

NM_139058.3(ARX):c.1150C>T (p.Arg384Cys)

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.1150C>T (p.Arg384Cys)

HGVS:

NC_000023.11:g.25007409G>A
NG_008281.1:g.13540C>T
NM_139058.3:c.1150C>TMANE SELECT
NP_620689.1:p.Arg384Cys
NC_000023.10:g.25025526G>A

Protein change:

R384C

Molecular consequence:

NM_139058.3:c.1150C>T - 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

Name:: Intellectual disability, X-linked, with or without seizures, arx-related (XLID29)
Synonyms:: MENTAL RETARDATION, X-LINKED 29; MENTAL RETARDATION, X-LINKED 32; MENTAL RETARDATION, X-LINKED 33; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010317; MedGen: C0796244; Orphanet: 777; OMIM: 300419

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003472624	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32383243, 33951346, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003472624

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 22, 2022)

germline

clinical testing

PubMed (3)
[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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Constraint and conservation of paired-type homeodomains predicts the clinical outcome of missense variants of uncertain significance.

Thai MHN, Gardner A, Redpath L, Mattiske T, Dearsley O, Shaw M, Vulto-van Silfhout AT, Pfundt R, Dixon J, McGaughran J, Pérez-Jurado LA, Gécz J, Shoubridge C.

Hum Mutat. 2020 Aug;41(8):1407-1424. doi: 10.1002/humu.24034. Epub 2020 Jun 2.

PubMed [citation]

PMID:: 32383243

Confirming the contribution and genetic spectrum of de novo mutation in infantile spasms: Evidence from a Chinese cohort.

Liu L, Liu F, Wang Q, Xie H, Li Z, Lu Q, Wang Y, Zhang M, Zhang Y, Picker J, Cui X, Zou L, Chen X.

Mol Genet Genomic Med. 2021 Jun;9(6):e1689. doi: 10.1002/mgg3.1689. Epub 2021 May 5.

PubMed [citation]

PMID:: 33951346
PMCID:: PMC8222834

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003472624.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 384 of the ARX protein (p.Arg384Cys). This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 32383243). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg384 amino acid residue in ARX. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33951346). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 ARX protein function.

#	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

Last Updated: Oct 8, 2024

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