Submissions for variant NM_139058.3(ARX):c.441_464dup (p.Ala148_Ala155dup)

dbSNP: rs398124510

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192670	SCV000246565	pathogenic	X-linked lissencephaly with abnormal genitalia	2014-10-02	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000082605	SCV000331088	pathogenic	not provided	2016-09-08	criteria provided, single submitter	clinical testing	This variant is the most common pathogenic repeat allele of the second poly-alanine tract (called PA2) 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 and X-linked infantile spasm syndrome among others.1-4 References: Kato et al. Am J Hum Genet. 2007 Aug;81(2):361-6. Stromme et al. Nat Genet. 2002 Apr;30(4):441-5 Gronskov et al. Eur J Hum Genet. 2004 Sep;12(9):701-5 Marques et al. Mol Genet Genomic Med. 2015 May;3(3):203-14
GeneDx	RCV000082605	SCV000564596	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Alanine repeat expansion in the second polyalanine tract of the ARX protein, extending the allele to 20 repeats; Published functional studies demonstrate a damaging effect as expansions in the second 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); Not observed in unaffected adult males referred for testing at GeneDx; This variant is associated with the following publications: (PMID: 22922607, 11889467, 24528893, 26029707, 24781210, 23246292, 12874418)
Invitae	RCV000813194	SCV000953539	pathogenic	Developmental and epileptic encephalopathy, 1; Intellectual disability, X-linked, with or without seizures, arx-related	2024-01-02	criteria provided, single submitter	clinical testing	This variant, c.441_464dup, results in the insertion of 8 amino acid(s) of the ARX protein (p.Ala148_Ala155dup), 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 Partington-like syndrome, West syndrome, and/or infantile spasms (PMID: 12874418, 22922607, 24781210, 26029707). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 96455). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ARX function (PMID: 23246292). This variant results in expansion of a poly-alanine tract in ARX. Expansions of the alanine tracts in ARX have been observed in individuals with ARX-related conditions (PMID: 11889467, 17664401, 23246292). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000082605	SCV001762117	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Molecular Genetics Lab, CHRU Brest	RCV003883129	SCV004697716	pathogenic	Developmental and epileptic encephalopathy, 1; Intellectual disability, X-linked, with or without seizures, arx-related; Corpus callosum agenesis-abnormal genitalia syndrome; X-linked lissencephaly with abnormal genitalia; Partington syndrome		criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000082605	SCV000218441	pathogenic	not provided	2015-01-30	no assertion criteria provided	clinical testing