rs104894743

Variant names:

• chrX-25012937-G-A
• rs104894743
• NM_139058.3:c.1058C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_139058.3(ARX):​c.1058C>T​(p.Pro353Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P353P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARX NM_139058.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.76
• Publications: 16 publications found

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]

ARX Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• intellectual disability, X-linked, with or without seizures, ARX-related

  Inheritance: XL Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
• Partington syndrome

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked lissencephaly with abnormal genitalia

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• corpus callosum agenesis-abnormal genitalia syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• infantile epileptic-dyskinetic encephalopathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked spasticity-intellectual disability-epilepsy syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_139058.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-25012937-G-A is Pathogenic according to our data. Variant chrX-25012937-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARX	NM_139058.3	c.1058C>T	p.Pro353Leu	missense_variant	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.1058C>T	p.Pro353Leu	missense_variant	Exon 2 of 5	1	NM_139058.3	ENSP00000368332.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1091876 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 359060

African (AFR) AF: 0.00 AC: 0 AN: 26309

American (AMR) AF: 0.00 AC: 0 AN: 34810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19271

East Asian (EAS) AF: 0.00 AC: 0 AN: 30054

South Asian (SAS) AF: 0.00 AC: 0 AN: 53086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39469

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3350

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839707

Other (OTH) AF: 0.00 AC: 0 AN: 45820

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 1 Pathogenic:2

Aug 13, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 29, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as hemizygous -

Inborn genetic diseases Pathogenic:1

May 07, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1058C>T (p.P353L) alteration is located in exon 2 (coding exon 2) of the ARX gene. This alteration results from a C to T substitution at nucleotide position 1058, causing the proline (P) at amino acid position 353 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported as hemizygous in multiple individuals and de novo in one individual with features consistent with ARX-related neurodevelopmental disorders (Strømme, 2002; Parrini, 2017; Wu, 2019; Yao, 2021). Of note, this variant has also been reported as heterozygous in females with non-syndromic intellectual disability (Wu, 2019). Two other alterations at the same codon, c.1058C>G (p.P353R) and c.1057C>T (p.P353S), have been detected in individuals with lissencephaly, ambiguous genitalia, epileptic encephalopathy, epileptic spasms, clonic seizures, severe developmental delay/intellectual disability, hypotonia, and/or spasticity (Kato, 2004; Papuc, 2019). This amino acid position is highly conserved in available vertebrate species. In vivo functional studies indicate this variant results in an increased susceptibility to seizures in a knock-in mouse model (Kitamura, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Corpus callosum agenesis-abnormal genitalia syndrome;C0796244:Intellectual disability, X-linked, with or without seizures, ARX-related;C0796250:Partington syndrome;C1846171:X-linked lissencephaly with abnormal genitalia;C3463992:Developmental and epileptic encephalopathy, 1 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Moderate+PS4+PP1_Strong+PM6_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	32
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.070	T
Polyphen		0.93	P
Vest4		0.89
MutPred		0.95		Loss of ubiquitination at K349 (P = 0.0496);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.95
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs104894743; hg19: chrX-25031054;