NM_139058.3(ARX):c.306GGC[17] (p.Ala109_Ala115dup) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jun 14, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000399003.15

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000344515	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Sep 7, 2016)	germline	clinical testing	Citation Link,
SCV000568027	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 14, 2021)	germline	clinical testing	Citation Link,
SCV001880728	Athena Diagnostics Inc	criteria provided, single submitter (Athena Diagnostics criteria)	Pathogenic (Jan 28, 2021)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 19605412, 26029707, 23583054, 21496008, 17664401, 15726411, 17490853, 29655203, 18462864, 11889467, 23246292, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000344515

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions)

Pathogenic
(Sep 7, 2016)

germline

clinical testing

Citation Link,

SCV000568027

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 14, 2021)

germline

clinical testing

Citation Link,

SCV001880728

Athena Diagnostics Inc

criteria provided, single submitter

(Athena Diagnostics criteria)

Pathogenic
(Jan 28, 2021)

unknown

clinical testing

PubMed (12)
[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	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach.

Marques I, Sá MJ, Soares G, Mota Mdo C, Pinheiro C, Aguiar L, Amado M, Soares C, Calado A, Dias P, Sousa AB, Fortuna AM, Santos R, Howell KB, Ryan MM, Leventer RJ, Sachdev R, Catford R, Friend K, Mattiske TR, Shoubridge C, Jorge P.

Mol Genet Genomic Med. 2015 May;3(3):203-14. doi: 10.1002/mgg3.133. Epub 2015 Feb 25.

PubMed [citation]

PMID:: 26029707
PMCID:: PMC4444162

See all PubMed Citations (12)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000344515.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

This variant is the most common pathogenic repeat allele of the first poly-alanine tract (referred to as PA1) within exon 2 of the ARX gene. This repeat allele has been reported with various nomenclatures in multiple individuals with ARX-related diseases including intellectual disability, Ohtahara syndrome and EIEE.1-4 References: Stromme et al. Nat Genet. 2002 Apr;30(4):441-5 Absoud et al. Dev Med Child Neurol. 2010 Mar;52(3):305-7. Kitamura et al. Hum Mol Genet. 2009 Oct 1;18(19):3708-24 Marques et al. Mol Genet Genomic Med. 2015 May;3(3):203-14

#	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		1	not provided	not provided	not provided

From GeneDx, SCV000568027.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Alanine repeat expansion in the first polyalanine tract of the ARX protein, extending the allele to 23 repeats; Published functional studies demonstrate a damaging effect as expansions in the first polyalanine repeat track are suggested to interfere with ARX-related regulation of KDM5C resulting in the misregulation of numerous downstream processes (Poeta et al., 2013 ); Published mouse models have also displayed severe seizures and learning disabilities (Kitamura et al., 2009); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11889467, 22628459, 19605412, 23246292)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics Inc, SCV001880728.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This duplication results in the addition of 7 alanines within the first poly-alanine tract of the ARX gene, and has been referred to by various nomenclatures in published literature, including (GCG)10+7, c.333_334(GCG)7, and c.330ins(GCG)7 (see PMID: 26029707). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated males with ARX-related disease, including both maternally inherited and apparent de novo cases. Assessment of experimental evidence suggests this variant results in abnormal protein function. Expression of this variant results in protein mislocalization and aggregation, and increased cell death (PMID: PMID: 17490853, 21496008). Mice carrying this variant display severe seizures and learning impairments (PMID: 19605412).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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