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NM_139058.3(ARX):c.306GGC[17] (p.Ala109_Ala115dup) AND Intellectual disability, X-linked, with or without seizures, arx-related

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 10, 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:
RCV003323356.8

Allele description [Variation Report for NM_139058.3(ARX):c.306GGC[17] (p.Ala109_Ala115dup)]

NM_139058.3(ARX):c.306GGC[17] (p.Ala109_Ala115dup)

Genes:
LOC109610631:aristaless related homeobox polyalanine expansion region [Gene]
ARX:aristaless related homeobox [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
Xp21.3
Genomic location:
Preferred name:
NM_139058.3(ARX):c.306GGC[17] (p.Ala109_Ala115dup)
Other names:
NP_620689.1:p.(Ala109_Ala115dup)
HGVS:
  • NC_000023.11:g.25013662CGC[17]
  • NG_008281.1:g.7260GGC[17]
  • NG_052655.1:g.233CGC[17]
  • NM_139058.3:c.306GGC[17]MANE SELECT
  • NP_620689.1:p.Ala109_Ala115dup
  • NC_000023.10:g.25031776_25031777insGCCGCCGCCGCCGCCGCCGCC
  • NC_000023.10:g.25031779CGC[17]
  • NM_139058.2:c.315_335dupGGCGGCGGCGGCGGCGGCGGC
  • NM_139058.3:c.315_335dupMANE SELECT
Links:
OMIM: 300382.0001; dbSNP: rs387906492
NCBI 1000 Genomes Browser:
rs387906492
Molecular consequence:
  • NM_139058.3:c.306GGC[17] - inframe_insertion - [Sequence Ontology: SO:0001821]

Condition(s)

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004029911Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jul 10, 2023) 		germlineclinical testing

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

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, Calvo M, Herrera-Ordonez N, Segura-Castel M, Diego-Alvarez D, Zawada M, Kandaswamy KK, Werber M, Paknia O, Zielske S, Ugrinovski D, Warnack G, Kampe K, Iurașcu MI, Cozma C, Vogel F, Alhashem A, et al.

Eur J Hum Genet. 2021 Jan;29(1):141-153. doi: 10.1038/s41431-020-00713-9. Epub 2020 Aug 28.

PubMed [citation]
PMID:
32860008
PMCID:
PMC7852664

Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice.

Kitamura K, Itou Y, Yanazawa M, Ohsawa M, Suzuki-Migishima R, Umeki Y, Hohjoh H, Yanagawa Y, Shinba T, Itoh M, Nakamura K, Goto Y.

Hum Mol Genet. 2009 Oct 1;18(19):3708-24. doi: 10.1093/hmg/ddp318. Epub 2009 Jul 15.

PubMed [citation]
PMID:
19605412
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004029911.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: ARX c.315_335dup21 (p.Ala109_Ala115dup) results in an in-frame duplication that is predicted to duplicate 7 amino acids into the encoded protein, resulting in an expansion of the first polyalanine tract of Arx. The variant was absent in 106683 control chromosomes (gnomAD v3.1.2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.315_335dup21 has been reported in the literature in multiple hemizygotes affected with AXR-Related Disorder, including several de novo occurrences (e.g., Mirzaa_2013, Bertoli-Avella_2021). These data indicate that the variant is very likely be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant lead to protein aggregation, mislocalization, and increased cell death in vitro (e.g., Masrallah_2004), and a mouse model of the variant displayed seizures as well as learning and memory defects (e.g., Kitamura_2009). The following publications have been ascertained in the context of this evaluation (PMID: 32860008, 23583054, 15533998, 19605412). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 10, 2024