ClinVar Genomic variation as it relates to human health
NM_000489.6(ATRX):c.736C>T (p.Arg246Cys)
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.736C>T (p.Arg246Cys)
Variation ID: 11735 Accession: VCV000011735.55
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq21.1 X: 77684520 (GRCh38) [ NCBI UCSC ] X: 76940012 (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 Dec 19, 2017 May 12, 2024 Oct 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000489.6:c.736C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000480.3:p.Arg246Cys missense NM_138270.5:c.622C>T NP_612114.2:p.Arg208Cys missense NC_000023.11:g.77684520G>A NC_000023.10:g.76940012G>A NG_008838.3:g.106750C>T LRG_1153:g.106750C>T LRG_1153t1:c.736C>T LRG_1153p1:p.Arg246Cys NP_000480.2:p.Arg246Cys - Protein change
- R246C, R208C
- Other names
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- Canonical SPDI
- NC_000023.11:77684519:G:A
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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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- Comment on variant
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 |
2248 | 2404 |
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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Oct 26, 2023 | RCV000012501.25 | |
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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May 19, 2022 | RCV000078972.33 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 3, 2013 | RCV000190796.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763634.3 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 3, 2022 | RCV001252427.3 | |
not provided (1) |
no classification provided
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- | RCV001249275.2 |
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
Help
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
(Oct 15, 2020)
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criteria provided, single submitter
Method: clinical testing
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Alpha thalassemia-X-linked intellectual disability syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001442634.1
First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020 |
Comment:
Variant summary: ATRX c.736C>T (p.Arg246Cys) results in a non-conservative amino acid change located in the ADD (Zinc finger) domain (IPR025766) of the encoded protein sequence. … (more)
Variant summary: ATRX c.736C>T (p.Arg246Cys) results in a non-conservative amino acid change located in the ADD (Zinc finger) domain (IPR025766) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 181349 control chromosomes. c.736C>T has been reported in the literature in multiple individuals affected with ATR-X Syndrome (example, Gibbons_1997, Wada_2000, Badens_2006, Pavone_2010, Monies_2019, Zhu_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=5)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(-)
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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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Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV001468949.1
First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
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Pathogenic
(Jul 01, 2023)
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criteria provided, single submitter
Method: research
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Alpha thalassemia-X-linked intellectual disability syndrome
Affected status: yes
Allele origin:
germline
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Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV004123046.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
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Pathogenic
(Oct 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Alpha thalassemia-X-linked intellectual disability syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001201707.6
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 246 of the ATRX protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 246 of the ATRX protein (p.Arg246Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alpha-thalassemia X-linked intellectual disability syndrome (PMID: 9326931, 16955409, 20500465, 24327140). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg129Cys. ClinVar contains an entry for this variant (Variation ID: 11735). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATRX protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 2018)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248379.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Nov 01, 2016)
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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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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781081.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Pathogenic
(Jan 30, 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: SCV000110837.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 19, 2017 |
Number of individuals with the variant: 5
Sex: mixed
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Acquired hemoglobin H disease
Alpha thalassemia-X-linked intellectual disability syndrome Intellectual disability-hypotonic facies syndrome, X-linked, 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894504.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447677.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hypospadias (present) , Wide mouth (present) , Microcephaly (present) , Micrognathia (present) , Telecanthus (present) , Hypotonia (present) , Global developmental delay (present)
Sex: male
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Pathogenic
(Sep 03, 2013)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000244237.6
First in ClinVar: Sep 14, 2015 Last updated: Dec 07, 2020 |
Comment:
​
Number of individuals with the variant: 1
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-hypotonic facies syndrome, X-linked, 1
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058254.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16955409, 20500465, 31130284, PS4_S). The variant was co-segregated with Mental retardation-hypotonic facies … (more)
The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16955409, 20500465, 31130284, PS4_S). The variant was co-segregated with Mental retardation-hypotonic facies syndrome, X-linked in multiple affected family members (PMID: 20500465, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.972, 3CNET: 0.905, PP3_P). A missense variant is a common mechanism associated with Mental retardation-hypotonic facies syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). A different missense change at the same codon has been reported to be associated with ATRX related disorder (PMID:10660327, PM5_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Wide nasal bridge (present) , Bulbous nose (present) , U-Shaped upper lip vermilion (present) , Eclabion (present) , Hyperreflexia (present) , Hypertelorism (present) , Hypertonia … (more)
Wide nasal bridge (present) , Bulbous nose (present) , U-Shaped upper lip vermilion (present) , Eclabion (present) , Hyperreflexia (present) , Hypertelorism (present) , Hypertonia (present) , Hyperventilation (present) , Intellectual disability, profound (present) , Long face (present) , Protruding ear (present) , Thick vermilion border (present) , Widely spaced teeth (present) (less)
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Pathogenic
(May 19, 2022)
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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: SCV000329092.7
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect (Iwase et al., 2011; Dhayalan et al., 2011); Not observed in large population cohorts (gnomAD); In silico analysis … (more)
Published functional studies demonstrate a damaging effect (Iwase et al., 2011; Dhayalan et al., 2011); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16955409, 27899421, 25590979, 9326931, 20500465, 24327140, 21666679, 21421568, 31130284, 32369273, 34051360, 17609377, 18409179) (less)
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Likely pathogenic
(Jan 01, 2019)
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no assertion criteria provided
Method: clinical testing
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Mental retardation-hypotonic facies syndrome X-linked, 1
Affected status: yes
Allele origin:
unknown
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001428183.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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X-linked alpha-thalassemia-mental retardation syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001452631.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951936.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968052.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Renier-Gabreels-Jasper syndrome
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV001423220.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Pathogenic and reported on 01-31-2016 by Lab or GTR ID 506634. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpretted as Pathogenic and reported on 01-31-2016 by Lab or GTR ID 506634. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Prenatal maternal abnormality (present) , Abnormality of the placenta (present) , Premature birth … (more)
Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Prenatal maternal abnormality (present) , Abnormality of the placenta (present) , Premature birth (present) , Abnormality of the neck (present) , Abnormality of the nose (present) , Abnormality of the skull (present) , Oral-pharyngeal dysphagia (present) , Abnormality of vision (present) , Abnormality of the optic nerve (present) , Mixed hearing impairment (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Memory impairment (present) , Movement disorder (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Abnormality of the musculature of the pelvis (present) , Abnormal pattern of respiration (present) , Feeding difficulties (present) , Abnormality of the large intestine (present) , Abnormality of the male genitalia (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Testing laboratory: Genotek, Genotek Ltd.
Date variant was reported to submitter: 2016-01-31
Testing laboratory interpretation: Pathogenic
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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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Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. | Zhu X | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25590979 |
[Mutation analysis for a Chinese family featuring X-linked alpha thalassemia/mental retardation syndrome]. | Lin SB | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2013 | PMID: 24327140 |
First case of dizygous twins with X-linked alpha-thalassemia/mental retardation syndrome showing wide clinical variability. | Pavone P | Pediatrics international : official journal of the Japan Pediatric Society | 2010 | PMID: 20500465 |
ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern. | Badens C | American journal of medical genetics. Part A | 2006 | PMID: 16955409 |
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 |
New mutations in XNP/ATR-X gene: a further contribution to genotype/phenotype relationship in ATR/X syndrome. Mutations in brief no. 176. Online. | Fichera M | Human mutation | 1998 | PMID: 10660327 |
Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain. | Gibbons RJ | Nature genetics | 1997 | PMID: 9326931 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATRX | - | - | - | - |
Text-mined citations for rs122445105 ...
HelpRecord last updated Jun 02, 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.
NCBI staff reviewed the sequence information reported in PubMed 9326931 Fig. 1b to determine the location of this allele on the current reference sequence.