NM_139058.3(ARX):c.1187dup (p.Gly397fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 11, 2020
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:: RCV001389322.7

Allele description [Variation Report for NM_139058.3(ARX):c.1187dup (p.Gly397fs)]

NM_139058.3(ARX):c.1187dup (p.Gly397fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

Xp21.3

Genomic location:

Preferred name:

NM_139058.3(ARX):c.1187dup (p.Gly397fs)

HGVS:

NC_000023.11:g.25007377dup
NG_008281.1:g.13577dup
NM_139058.3:c.1187dupMANE SELECT
NP_620689.1:p.Gly397fs
NC_000023.10:g.25025488_25025489insG
NC_000023.10:g.25025494dup
NM_139058.2:c.1187dup
NM_139058.2:c.1187dupC

Note:

ClinGen staff contributed the HGVS expression for this variant.

Protein change:

G397fs

Links:

OMIM: 300382.0009; dbSNP: rs1328291159

NCBI 1000 Genomes Browser:

rs1328291159

Molecular consequence:

NM_139058.3:c.1187dup - frameshift variant - [Sequence Ontology: SO:0001589]

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

Recent activity

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methyltransferase-like protein 22 isoform X1 [Cucumis sativus]
methyltransferase-like protein 22 isoform X1 [Cucumis sativus]
gi|778681359|ref|XP_011651493.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001590645	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 11, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12379852, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001590645

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 11, 2020)

germline

clinical testing

PubMed (2)
[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

Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans.

Kitamura K, Yanazawa M, Sugiyama N, Miura H, Iizuka-Kogo A, Kusaka M, Omichi K, Suzuki R, Kato-Fukui Y, Kamiirisa K, Matsuo M, Kamijo S, Kasahara M, Yoshioka H, Ogata T, Fukuda T, Kondo I, Kato M, Dobyns WB, Yokoyama M, Morohashi K.

Nat Genet. 2002 Nov;32(3):359-69. Epub 2002 Oct 15.

PubMed [citation]

PMID:: 12379852

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001590645.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change results in a premature translational stop signal in the ARX gene (p.Gly397Trpfs*135). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 166 amino acids of the ARX protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with X-linked lissencephaly with ambiguous genitalia (PMID: 12379852). ClinVar contains an entry for this variant (Variation ID: 11194). This variant disrupts the C-terminus of the ARX protein. Other variant(s) that disrupt this region (p.Arg527*) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. 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

Last Updated: Oct 8, 2024

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