ClinVar Genomic variation as it relates to human health
NM_000489.6(ATRX):c.536A>G (p.Asn179Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000489.6(ATRX):c.536A>G (p.Asn179Ser)
Variation ID: 93141 Accession: VCV000093141.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq21.1 X: 77688876 (GRCh38) [ NCBI UCSC ] X: 76944369 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 8, 2017 May 16, 2022 May 4, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000489.6:c.536A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000480.3:p.Asn179Ser missense NM_138270.5:c.422A>G NP_612114.2:p.Asn141Ser missense NC_000023.11:g.77688876T>C NC_000023.10:g.76944369T>C NG_008838.3:g.102394A>G LRG_1153:g.102394A>G NP_000480.2:p.Asn179Ser - Protein change
- N179S, N141S
- Other names
- NM_000489.5(ATRX):c.536A>G
- Canonical SPDI
- NC_000023.11:77688875:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ATRX | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2277 | 2439 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 2, 2016 | RCV000078965.8 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 4, 2022 | RCV000850379.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 22, 2022 | RCV001262503.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 03, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000110830.8
First in ClinVar: Jan 17, 2014 Last updated: Mar 08, 2017 |
Number of individuals with the variant: 6
Sex: mixed
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Alpha thalassemia-X-linked intellectual disability syndrome
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440409.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Likely pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: curation
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Intellectual disability-hypotonic facies syndrome, X-linked, 1
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV002507048.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
The hemizygous p.Asn179Ser variant in ATRX was identified by our study in 3 siblings with x-linked mental retardation-hypotonic facies syndrome. This variant is assumed de … (more)
The hemizygous p.Asn179Ser variant in ATRX was identified by our study in 3 siblings with x-linked mental retardation-hypotonic facies syndrome. This variant is assumed de novo in 1 individual, but maternity and paternity have not been confirmed (PMID: 16813605). The variant has been reported in at least 5 individuals of Japanese and unknown ethnicity with x-linked mental retardation-hypotonic facies syndrome (PMID: 16813605, 10995512, 8968741, 25252072, 33229608), but was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 93141) as pathogenic by GeneDx, HudsonAlpha Institute for Biotechnology, and EGL Genetic Diagnostics, Eurofins Clinical Diagnostics. In vitro functional studies provide some evidence that the p.Asn179Ser variant may slightly impact protein function (PMID: 8968741). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in ATRX in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM6, PP2, PP3, PS4_supporting, PS3_supporting (Richards 2015). (less)
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Pathogenic
(Jun 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000520865.3
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The c.536 A>G pathogenic variant in the ATRX gene has been reported previously in association with ATRX-related disorders (Picketts et al., 1996; Badens et al., … (more)
The c.536 A>G pathogenic variant in the ATRX gene has been reported previously in association with ATRX-related disorders (Picketts et al., 1996; Badens et al., 2006; Wada et al., 2000). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies indicate that c.536 A>G creates a cryptic splice donor site, leading to a deletion of 63 nucleotides (reported as A751G using alternate nomenclature in Villard et al., 1997; reported as A869G using alternate nomenclature in Picketts et al., 1996). This substitution occurs in the ADD domain and pathogenic variants affecting this domain are presumed to have structural consequences on the ATRX protein and impact histone methylation (Argentaro et al., 2007; Iwase et al., 2011; Stenson et al., 2014). (less)
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Pathogenic
(Jun 25, 2019)
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criteria provided, single submitter
Method: research
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Intellectual disability-hypotonic facies syndrome, X-linked, 1
Affected status: yes
Allele origin:
maternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI_WGS
Accession: SCV000992564.1 First in ClinVar: Sep 20, 2019 Last updated: Sep 20, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Postaxial polydactyly (present) , Flexion contracture (present) , Brachydactyly (present) , Pes planus (present) , Pes valgus (present) , Pectus carinatum (present) , Aplasia cutis … (more)
Postaxial polydactyly (present) , Flexion contracture (present) , Brachydactyly (present) , Pes planus (present) , Pes valgus (present) , Pectus carinatum (present) , Aplasia cutis congenita (present) (less)
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Alpha thalassemia-X-linked intellectual disability syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318488.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
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). … (more)
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. (less)
Clinical Features:
Astigmatism (present) , Atrial septal defect (present) , Brisk reflexes (present) , Full cheeks (present) , Drooling (present) , Dry skin (present) , Generalized hypopigmentation … (more)
Astigmatism (present) , Atrial septal defect (present) , Brisk reflexes (present) , Full cheeks (present) , Drooling (present) , Dry skin (present) , Generalized hypopigmentation (present) , Finger clinodactyly (present) , Depressed nasal bridge (present) , Camptodactyly of finger (present) , Global developmental delay (present) , Hypertelorism (present) , Hypospadias (present) , Generalized hypotonia (present) , Cutis laxa (present) , Long philtrum (present) , Myopia (present) , Microdontia (present) , Smooth philtrum (present) , Tented upper lip vermilion (present) , Widely spaced teeth (present) , Intellectual disability (present) (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mutations in the chromatin-associated protein ATRX. | Gibbons RJ | Human mutation | 2008 | PMID: 18409179 |
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 | Clinical genetics | 2006 | PMID: 16813605 |
Molecular genetic study of japanese patients with X-linked alpha-thalassemia/mental retardation syndrome (ATR-X). | Wada T | American journal of medical genetics | 2000 | PMID: 10995512 |
Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase. | Villard L | Genomics | 1997 | PMID: 9244431 |
ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome. | Picketts DJ | Human molecular genetics | 1996 | PMID: 8968741 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATRX | - | - | - | - |
Text-mined citations for rs398123425 ...
HelpRecord last updated Mar 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.