VCV000011186.29 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 11186 Accession: VCV000011186.29

Type and length

Microsatellite, 21 bp

Location

Cytogenetic: Xp21.3 X: 25013659-25013660 (GRCh38) [ NCBI UCSC ] X: 25031776-25031777 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 5, 2015	Sep 16, 2024	Dec 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_139058.3:c.306GGC[17] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_620689.1:p.Ala109_Ala115dup	inframe insertion
NM_139058.3:c.315_335dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_139058.2:c.315_335dupGGCGGCGGCGGCGGCGGCGGC
NC_000023.11:g.25013662CGC[17]
NC_000023.10:g.25031779CGC[17]
NG_008281.1:g.7260GGC[17]
NG_052655.1:g.233CGC[17]

... more HGVS ... less HGVS

Protein change

Other names

NP_620689.1:p.(Ala109_Ala115dup)

Canonical SPDI

NC_000023.11:25013659:GCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC:GCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA213330 OMIM: 300382.0001 dbSNP: rs387906492 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ARX		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	697	1029
LOC109610631	-	-	-	GRCh38	-	240

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Developmental and epileptic encephalopathy, 1	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 22, 2022	RCV000011936.31
X-linked lissencephaly with abnormal genitalia	Pathogenic (1)	criteria provided, single submitter	Nov 6, 2014	RCV000193540.13
Developmental and epileptic encephalopathy, 1 Intellectual disability, X-linked, with or without seizures, arx-related	Pathogenic (1)	criteria provided, single submitter	Dec 11, 2023	RCV000456891.17
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000399003.17
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Apr 8, 2017	RCV002316190.9
Intellectual disability, X-linked, with or without seizures, arx-related	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2023	RCV003323356.8
West syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 15, 2023	RCV003488334.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 06, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lissencephaly, X-linked 2 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000246560.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Pathogenic (Sep 07, 2016)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000344515.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 Comment: 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. … (more) 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 (less)	Other databases http://geneticslab.emory.edu/emv… http://geneticslab.emory.edu/emvclass/emvclass.php?approved_symbol=ARX Comment: 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. … (more) 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 (less) Number of individuals with the variant: 1 Sex: mixed
Likely pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 1 Affected status: yes Allele origin: germline	3billion Accession: SCV002520984.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Comment: This variant has been reported as pathogenic more than twice (ClinVar ID: VCV000011186), along with assertion criteria based on the ACMG guidelines. It is absent … (more) This variant has been reported as pathogenic more than twice (ClinVar ID: VCV000011186), along with assertion criteria based on the ACMG guidelines. It is absent from the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Brisk reflexes (present) , Dystonic disorder (present) , Seizure (present) , Global developmental delay (present) , Sleep abnormality (present)
Pathogenic (Dec 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	West syndrome Affected status: yes Allele origin: maternal	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan Accession: SCV004232654.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Comment: Zygosity: Hemizygosis Number of individuals with the variant: 1 Sex: male Geographic origin: Argentina
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 1 Affected status: yes Allele origin: de novo	Centogene AG - the Rare Disease Company Accession: SCV001426447.1 First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020
Pathogenic (Jan 28, 2021)	criteria provided, single submitter (Athena Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001880728.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Publications: PubMed (11) PubMed: 19605412‚ 26029707‚ 23583054‚ 21496008‚ 17664401‚ 15726411‚ 17490853‚ 29655203‚ 18462864‚ 11889467‚ 23246292 Comment: 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 … (more) 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). (less)
Pathogenic (Jul 10, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Intellectual disability, X-linked, with or without seizures, arx-related Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004029911.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Publications: PubMed (4) PubMed: 32860008‚ 19605412‚ 23583054‚ 15533998 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 11, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Developmental and epileptic encephalopathy, 1 Intellectual disability, X-linked, with or without seizures, arx-related Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000551640.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 11889467‚ 15726411‚ 17664401‚ 26029707‚ 17490853‚ 23246292 Comment: This variant, c.315_335dup, results in the insertion of 7 amino acid(s) of the ARX protein (p.Ala109_Ala115dup), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.315_335dup, results in the insertion of 7 amino acid(s) of the ARX protein (p.Ala109_Ala115dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has been observed in individual(s) with early-onset epilepsy (PMID: 11889467, 15726411, 17664401, 26029707). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.333_334ins(GCG)7 and (GCG)10+7. ClinVar contains an entry for this variant (Variation ID: 11186). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ARX function (PMID: 17490853, 23246292). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 08, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000851643.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 11889467‚ 15533998‚ 21496008‚ 23583054 Comment: The c.315_335dup21 pathogenic mutation (also known as p.A109_A115dup), located in coding exon 2 of the ARX gene, results from an in-frame duplication of 21 nucleotides … (more) The c.315_335dup21 pathogenic mutation (also known as p.A109_A115dup), located in coding exon 2 of the ARX gene, results from an in-frame duplication of 21 nucleotides at nucleotide positions 315 to 335. This results in the duplication of 7 extra residues (AAAAAAA) between codons 109 and 115, leading to an expansion of the first polyalanine tract from 16 to 23. This mutation was originally reported as (GCG)10+7 in two families with X-linked infantile spasm syndrome and West syndrome (Strømme et al. Nat Genet. 2002 Apr;30(4):441-5). De novo occurrences of the mutation (described as c.333_334ins[GCG]7 and c.333_335dup(GGC)7) were also reported in multiple patients with mental retardation, dystonia, infantile-onset refractory epilepsy, and/or developmental delay (Guerrini et al. Neurology. 2007 Jul 31;69(5):427-33; Mirzaa et al. Pediatr. Neurol. 2013 May;48(5):367-77). In addition, expression of ARX protein harboring the 23 alanines was shown to cause protein aggregation, cell death, and mislocalization (Nasrallah et al. J Cell Biol. 2004 Nov 8;167(3):411-6; Fullston et al. Clin. Genet. 2011 Dec;80(6):510-22). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Dec 01, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568027.5 First in ClinVar: Dec 06, 2016 Last updated: Sep 16, 2024	Comment: 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 … (more) 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 (PMID: 23246292); Published mouse models have also displayed severe seizures and learning disabilities (PMID: 19605412); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11889467, 22628459, 36571524, 17664401, 23583054, 21496008, 15726411, 26029707, 17490853, 20300201, 23246292, 19605412) (less)
Pathogenic (Jul 31, 2007)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032169.5 First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2020	Publications: PubMed (5) PubMed: 11889467‚ 10334471‚ 9307258‚ 17490853‚ 17664401 Comment on evidence: In 2 unrelated families, 1 Canadian and 2 Belgian, with developmental and epileptic encephalopathy (DEE1; 308350), described as infantile spasm syndrome, Stromme et al. (2002) … (more) In 2 unrelated families, 1 Canadian and 2 Belgian, with developmental and epileptic encephalopathy (DEE1; 308350), described as infantile spasm syndrome, Stromme et al. (2002) found that 8 and 2 male affected members, respectively, had an additional stretch of 7 tandem GCG repeats within the normal stretch of 10 GCG triplet repeats in exon 2. These families had been described by Bruyere et al. (1999) and Claes et al. (1997). The effect of the mutation on the protein product was polyalanine expansion. The haplotype background of the mutation was different in the 2 families, indicating that a recurrent mutation had occurred. The normal tract of 16 alanine residues (amino acids 100-115) was expanded to 23. Shoubridge et al. (2007) showed that this polyalanine expansion mutation was associated with an increased propensity of ARX protein aggregation and a shift from nuclear to cytoplasmic localization. Guerrini et al. (2007) identified the (GCG)10+7 expansion in 6 boys, including 2 pairs of brothers, with a severe form of DEE1, which they termed infantile epileptic-dyskinetic encephalopathy, including chorea and dystonia. All 6 boys also had severe mental retardation. Seizure onset occurred between 2 and 5 months of age and earlier than dystonia, which was severe and progressed to quadriplegic dyskinesia. Three children had recurrent, life-threatening status dystonicus. Brain MRI showed basal ganglia abnormalities in 4 patients. (less)
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Comment:

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

Comment:

This variant has been reported as pathogenic more than twice (ClinVar ID: VCV000011186), along with assertion criteria based on the ACMG guidelines. It is absent from the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

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).

Comment:

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.

Comment:

This variant, c.315_335dup, results in the insertion of 7 amino acid(s) of the ARX protein (p.Ala109_Ala115dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has been observed in individual(s) with early-onset epilepsy (PMID: 11889467, 15726411, 17664401, 26029707). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.333_334ins(GCG)7 and (GCG)10+7. ClinVar contains an entry for this variant (Variation ID: 11186). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ARX function (PMID: 17490853, 23246292). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.315_335dup21 pathogenic mutation (also known as p.A109_A115dup), located in coding exon 2 of the ARX gene, results from an in-frame duplication of 21 nucleotides at nucleotide positions 315 to 335. This results in the duplication of 7 extra residues (AAAAAAA) between codons 109 and 115, leading to an expansion of the first polyalanine tract from 16 to 23. This mutation was originally reported as (GCG)10+7 in two families with X-linked infantile spasm syndrome and West syndrome (Strømme et al. Nat Genet. 2002 Apr;30(4):441-5). De novo occurrences of the mutation (described as c.333_334ins[GCG]7 and c.333_335dup(GGC)7) were also reported in multiple patients with mental retardation, dystonia, infantile-onset refractory epilepsy, and/or developmental delay (Guerrini et al. Neurology. 2007 Jul 31;69(5):427-33; Mirzaa et al. Pediatr. Neurol. 2013 May;48(5):367-77). In addition, expression of ARX protein harboring the 23 alanines was shown to cause protein aggregation, cell death, and mislocalization (Nasrallah et al. J Cell Biol. 2004 Nov 8;167(3):411-6; Fullston et al. Clin. Genet. 2011 Dec;80(6):510-22). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

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 (PMID: 23246292); Published mouse models have also displayed severe seizures and learning disabilities (PMID: 19605412); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11889467, 22628459, 36571524, 17664401, 23583054, 21496008, 15726411, 26029707, 17490853, 20300201, 23246292, 19605412)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.	Bertoli-Avella AM	European journal of human genetics : EJHG	2021	PMID: 32860008
Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders.	Lindy AS	Epilepsia	2018	PMID: 29655203
Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach.	Marques I	Molecular genetics & genomic medicine	2015	PMID: 26029707
CDKL5 and ARX mutations in males with early-onset epilepsy.	Mirzaa GM	Pediatric neurology	2013	PMID: 23583054
A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX.	Poeta L	American journal of human genetics	2013	PMID: 23246292
Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene.	Fullston T	Clinical genetics	2011	PMID: 21496008
Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice.	Kitamura K	Human molecular genetics	2009	PMID: 19605412
Expansion of the ARX spectrum.	Wallerstein R	Clinical neurology and neurosurgery	2008	PMID: 18462864
Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus.	Guerrini R	Neurology	2007	PMID: 17664401
Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene.	Shoubridge C	Genomics	2007	PMID: 17490853
Familial West syndrome and dystonia caused by an Aristaless related homeobox gene mutation.	Wohlrab G	European journal of pediatrics	2005	PMID: 15726411
A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death.	Nasrallah IM	The Journal of cell biology	2004	PMID: 15533998
Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy.	Strømme P	Nature genetics	2002	PMID: 11889467
Confirmation of linkage in X-linked infantile spasms (West syndrome) and refinement of the disease locus to Xp21.3-Xp22.1.	Bruyere H	Clinical genetics	1999	PMID: 10334471
The X-linked infantile spasms syndrome (MIM 308350) maps to Xp11.4-Xpter in two pedigrees.	Claes S	Annals of neurology	1997	PMID: 9307258
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Text-mined citations for rs387906492 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387906492 ...