NM_139058.3(ARX):c.988C>T (p.Arg330Cys) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 31, 2023
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:: RCV003810555.2

Allele description [Variation Report for NM_139058.3(ARX):c.988C>T (p.Arg330Cys)]

NM_139058.3(ARX):c.988C>T (p.Arg330Cys)

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.988C>T (p.Arg330Cys)

HGVS:

NC_000023.11:g.25013007G>A
NG_008281.1:g.7942C>T
NM_139058.3:c.988C>TMANE SELECT
NP_620689.1:p.Arg330Cys
NC_000023.10:g.25031124G>A

Protein change:

R330C

Molecular consequence:

NM_139058.3:c.988C>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
SCV004610510	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 31, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31324350, 31791873, 35121198, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004610510

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 31, 2023)

germline

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

ARX-associated infantile epileptic-dyskinetic encephalopathy with responsiveness to valproate for controlling seizures and reduced activity of muscle mitochondrial complex IV.

Kwong AK, Chu VL, Rodenburg RJT, Smeitink J, Fung CW.

Brain Dev. 2019 Nov;41(10):883-887. doi: 10.1016/j.braindev.2019.07.003. Epub 2019 Jul 16.

PubMed [citation]

PMID:: 31324350

Genotype-phenotype correlation on 45 individuals with West syndrome.

Krey I, Krois-Neudenberger J, Hentschel J, Syrbe S, Polster T, Hanker B, Fiedler B, Kurlemann G, Lemke JR.

Eur J Paediatr Neurol. 2020 Mar;25:134-138. doi: 10.1016/j.ejpn.2019.11.010. Epub 2019 Nov 26.

PubMed [citation]

PMID:: 31791873

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004610510.1

#	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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 330 of the ARX protein (p.Arg330Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ARX-related conditions (Invitae). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg330 amino acid residue in ARX. Other variant(s) that disrupt this residue have been observed in individuals with ARX-related conditions (PMID: 31324350, 31791873, 35121198), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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