X-25013659-TGCCGCCGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chrX-25013659-T-TGCCGCCGCCGCCGCCGCCGCCGCC
• rs387906492
• NM_139058.3:c.312_335dupGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP3

The NM_139058.3(ARX):​c.312_335dupGGCGGCGGCGGCGGCGGCGGCGGC​(p.Ala105_Ala112dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARX NM_139058.3 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.33

Genes affected

ARX (HGNC:18060): (aristaless related homeobox) This gene is a homeobox-containing gene expressed during development. The expressed protein contains two conserved domains, a C-peptide (or aristaless domain) and the prd-like class homeobox domain. It is a member of the group-II aristaless-related protein family whose members are expressed primarily in the central and/or peripheral nervous system. This gene is thought to be involved in CNS development. Expansion of a polyalanine tract and other mutations in this gene cause X-linked cognitive disability and epilepsy. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-25013659-T-TGCCGCCGCCGCCGCCGCCGCCGCC is Pathogenic according to our data. Variant chrX-25013659-T-TGCCGCCGCCGCCGCCGCCGCCGCC is described in ClinVar as [Pathogenic]. Clinvar id is 210327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP3: Nonframeshift variant in repetitive region in NM_139058.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3	c.312_335dupGGCGGCGGCGGCGGCGGCGGCGGC	p.Ala105_Ala112dup	disruptive_inframe_insertion	Exon 2 of 5	ENST00000379044.5	NP_620689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARX	ENST00000379044.5	c.312_335dupGGCGGCGGCGGCGGCGGCGGCGGC	p.Ala105_Ala112dup	disruptive_inframe_insertion	Exon 2 of 5	1	NM_139058.3	ENSP00000368332.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked lissencephaly with abnormal genitalia Pathogenic:1

Nov 06, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, X-linked, with or without seizures, arx-related;C3463992:Developmental and epileptic encephalopathy, 1 Pathogenic:1

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.312_335dup24, results in the insertion of 8 amino acid(s) of the ARX protein (p.Ala108_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 ARX-related conditions (PMID: 11889467, 17664401, 23246292). This variant is also known as c.333_335dup(GGC)8. ClinVar contains an entry for this variant (Variation ID: 210327). 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: 15533998). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906492; hg19: chrX-25031776;