NM_139058.3(ARX):c.1555_1556insGG (p.Asp519fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 10, 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:: RCV000794657.6

Allele description [Variation Report for NM_139058.3(ARX):c.1555_1556insGG (p.Asp519fs)]

NM_139058.3(ARX):c.1555_1556insGG (p.Asp519fs)

Gene:

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

Variant type:

Insertion

Cytogenetic location:

Xp21.3

Genomic location:

Preferred name:

NM_139058.3(ARX):c.1555_1556insGG (p.Asp519fs)

HGVS:

NC_000023.11:g.25004804_25004805insCC
NG_008281.1:g.16145_16146insGG
NM_139058.3:c.1555_1556insGGMANE SELECT
NP_620689.1:p.Asp519fs
NC_000023.10:g.25022920_25022921insCC
NC_000023.10:g.25022921_25022922insCC
NM_139058.2:c.1555_1556insGG

Protein change:

D519fs

Links:

dbSNP: rs1601945655

NCBI 1000 Genomes Browser:

rs1601945655

Molecular consequence:

NM_139058.3:c.1555_1556insGG - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000934078	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 10, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31623504, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000934078

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 10, 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

Diagnostic and Clinical Utility of Clinical Exome Sequencing in Children With Moderate and Severe Global Developmental Delay / Intellectual Disability.

Stojanovic JR, Miletic A, Peterlin B, Maver A, Mijovic M, Borlja N, Dimitrijevic B, Soldatovic I, Cuturilo G.

J Child Neurol. 2020 Feb;35(2):116-131. doi: 10.1177/0883073819879835. Epub 2019 Oct 17.

PubMed [citation]

PMID:: 31623504

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000934078.4

#	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.Asp519Glyfs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 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 not been reported in the literature in individuals with ARX-related conditions. This variant disrupts the C-terminus of the ARX protein. Other variant(s) that disrupt this region (p.Arg527Alafs*5) have been determined to be pathogenic (PMID: 31623504). 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: Mar 5, 2024

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