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NM_000489.6(ATRX):c.4825C>T (p.His1609Tyr) AND Alpha thalassemia-X-linked intellectual disability syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 2, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV003397224.1

Allele description [Variation Report for NM_000489.6(ATRX):c.4825C>T (p.His1609Tyr)]

NM_000489.6(ATRX):c.4825C>T (p.His1609Tyr)

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.4825C>T (p.His1609Tyr)
HGVS:
  • NC_000023.11:g.77633697G>A
  • NG_008838.3:g.157573C>T
  • NM_000489.6:c.4825C>TMANE SELECT
  • NM_138270.5:c.4711C>T
  • NP_000480.3:p.His1609Tyr
  • NP_000480.3:p.His1609Tyr
  • NP_612114.2:p.His1571Tyr
  • LRG_1153t1:c.4825C>T
  • LRG_1153:g.157573C>T
  • LRG_1153p1:p.His1609Tyr
  • NC_000023.10:g.76889185G>A
  • NM_000489.5:c.4825C>T
Protein change:
H1571Y
Molecular consequence:
  • NM_000489.6:c.4825C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_138270.5:c.4711C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004102752Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Nov 2, 2023) 		maternalclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedmaternalyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).

Gibbons RJ, Picketts DJ, Villard L, Higgs DR.

Cell. 1995 Mar 24;80(6):837-45.

PubMed [citation]
PMID:
7697714

Mutations in the chromatin-associated protein ATRX.

Gibbons RJ, Wada T, Fisher CA, Malik N, Mitson MJ, Steensma DP, Fryer A, Goudie DR, Krantz ID, Traeger-Synodinos J.

Hum Mutat. 2008 Jun;29(6):796-802. doi: 10.1002/humu.20734.

PubMed [citation]
PMID:
18409179
See all PubMed Citations (4)

Details of each submission

From Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen, SCV004102752.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedclinical testing PubMed (4)

Description

The variant has not been detected in the general population (gnomAD). It has not yet been described in the literature or in the ClinVar and dbSNP151 databases. Another amino acid substitution at this position (NM_000489.6:c.4826A>G, p.(His1609Arg)) has already been reported in a patient with ATRX syndrome (PMID: 7697714, PMID: 18409179) and is listed twice in ClinVar as (likely) pathogenic (Variation ID 11721). The variant is located in a mutational hotspot in the Snf2 domain and a destabilizing effect on the ATRX protein has been demonstrated for mutations of the highly conserved amino acid His1609. (PMID: 21505078) Bioinformatically, the change is classified as "probably disease-causing" (PolyPhen2, mutation taster, SIFT; CADDphred 27.8). The variant is currently considered as likely pathogenic (ACMG criteria).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Nov 25, 2023