NM_000489.6(ATRX):c.536A>G (p.Asn179Ser) AND Alpha thalassemia-X-linked intellectual disability syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 22, 2022
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:: RCV001262503.2

Allele description [Variation Report for NM_000489.6(ATRX):c.536A>G (p.Asn179Ser)]

NM_000489.6(ATRX):c.536A>G (p.Asn179Ser)

Gene:

ATRX:ATRX chromatin remodeler [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq21.1

Genomic location:

Preferred name:

NM_000489.6(ATRX):c.536A>G (p.Asn179Ser)

Other names:

NM_000489.5(ATRX):c.536A>G

HGVS:

NC_000023.11:g.77688876T>C
NG_008838.3:g.102394A>G
NM_000489.6:c.536A>GMANE SELECT
NM_138270.5:c.422A>G
NP_000480.3:p.Asn179Ser
NP_612114.2:p.Asn141Ser
LRG_1153:g.102394A>G
NC_000023.10:g.76944369T>C
NM_000489.3:c.536A>G
NM_000489.4:c.536A>G
NP_000480.2:p.Asn179Ser

Protein change:

N141S

Links:

dbSNP: rs398123425

NCBI 1000 Genomes Browser:

rs398123425

Molecular consequence:

NM_000489.6:c.536A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_138270.5:c.422A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Alpha thalassemia-X-linked intellectual disability syndrome (ATRX)
Synonyms:: ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED; ATR-X syndrome; Alpha thalassemia mental retardation syndrome, nondeletion type, X-linked; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010519; MedGen: C1845055; Orphanet: 847; OMIM: 301040

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001440409	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002318488	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16813605, 10995512, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001440409

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 1, 2019)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002318488

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 22, 2022)

germline

clinical testing

PubMed (3)
[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	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Mutations in PHD-like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome.

Badens C, Lacoste C, Philip N, Martini N, Courrier S, Giuliano F, Verloes A, Munnich A, Leheup B, Burglen L, Odent S, Van Esch H, Levy N.

Clin Genet. 2006 Jul;70(1):57-62.

PubMed [citation]

PMID:: 16813605

Molecular genetic study of japanese patients with X-linked alpha-thalassemia/mental retardation syndrome (ATR-X).

Wada T, Kubota T, Fukushima Y, Saitoh S.

Am J Med Genet. 2000 Sep 18;94(3):242-8.

PubMed [citation]

PMID:: 10995512

See all PubMed Citations (3)

Details of each submission

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440409.1

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

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

From 3billion, SCV002318488.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093141, PMID:10995512). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16813605). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.745>=0.6, SPLICEAI: 0.68). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Oct 13, 2024

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