ClinVar Genomic variation as it relates to human health
NM_000489.6(ATRX):c.109C>T (p.Arg37Ter)
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.109C>T (p.Arg37Ter)
Variation ID: 11742 Accession: VCV000011742.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq21.1 X: 77717155 (GRCh38) [ NCBI UCSC ] X: 76972632 (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 Apr 4, 2013 Jun 9, 2024 Jun 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000489.6:c.109C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000480.3:p.Arg37Ter nonsense NM_000489.5:c.109C>T NM_138270.5:c.109C>T NP_612114.2:p.Arg37Ter nonsense NC_000023.11:g.77717155G>A NC_000023.10:g.76972632G>A NG_008838.3:g.74115C>T LRG_1153:g.74115C>T - Protein change
- R37*
- Other names
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- Canonical SPDI
- NC_000023.11:77717154: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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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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Intellectual disability-hypotonic facies syndrome, X-linked
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Pathogenic (1) |
no assertion criteria provided
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Dec 1, 2004 | RCV000012508.32 |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 23, 2023 | RCV000148028.17 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 13, 2019 | RCV000224314.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 2, 2021 | RCV000680146.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 27, 2019 | RCV002444427.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 12, 2022 | RCV003151722.8 |
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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Likely pathogenic
(Feb 13, 2019)
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criteria provided, single submitter
Method: research
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Intellectual disability
Affected status: yes
Allele origin:
unknown
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Raymond Lab, University of Cambridge
Accession: SCV000897756.1
First in ClinVar: Sep 16, 2019 Last updated: Sep 16, 2019 |
Number of individuals with the variant: 2
Family history: yes
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Pathogenic
(Oct 02, 2021)
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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: SCV002012304.1
First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011742.7). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Delayed gross motor development (present) , Premature birth (present) , Abnormal lip morphology (present) , Delayed speech and language development (present) , Hypertelorism (present) , … (more)
Delayed gross motor development (present) , Premature birth (present) , Abnormal lip morphology (present) , Delayed speech and language development (present) , Hypertelorism (present) , Specific learning disability (present) , Nephrolithiasis (present) , Attention deficit hyperactivity disorder (present) , Depressed nasal bridge (present) , Autistic behavior (present) , Proximal tubulopathy (present) , Fetal growth restriction (present) , Intellectual disability (present) (less)
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Pathogenic
(Jun 23, 2021)
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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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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512243.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PP1 very strong
Geographic origin: Brazil
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Pathogenic
(Jul 25, 2014)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability
Affected status: yes
Allele origin:
maternal
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Diagnostic Laboratory, Strasbourg University Hospital
Accession: SCV000281747.1
First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Jan 01, 2014)
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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:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000965785.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
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Pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-hypotonic facies syndrome, X-linked, 1
(X-linked inheritance)
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV000807591.2
First in ClinVar: Sep 17, 2018 Last updated: Dec 11, 2022 |
Comment:
This mutation has been previously reported as disease-causing and was found once in our laboratory in an 8-year-old male with intellectual disability, hypotonia, dysmorphic features, … (more)
This mutation has been previously reported as disease-causing and was found once in our laboratory in an 8-year-old male with intellectual disability, hypotonia, dysmorphic features, GERD, febrile seizure, short stature, mirocephaly. (less)
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Pathogenic
(May 25, 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: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769265.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with both X-linked dominant and recessive disease (OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 35). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other NMD-predicted variants have previously been reported as pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in more than 20 male patients with intellectual disability (ClinVar, PMID: 26350204, PMID: 24805811). (P) 0901 - Strong evidence for segregation with disease. The variant has been shown to segregate with disease in affected males in at least 5 families, with unaffected female carriers (PMID: 24805811). (P) 1102 - Strong phenotype match. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Sep 12, 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: SCV003840738.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
Segregates with X-linked intellectual disability, short stature, microcephaly, and dysmorphic features in multiple families; the heterozygous unaffected females showed skewed X-inactivation (Abidi et al., 2005; … (more)
Segregates with X-linked intellectual disability, short stature, microcephaly, and dysmorphic features in multiple families; the heterozygous unaffected females showed skewed X-inactivation (Abidi et al., 2005; Basehore et al., 2015); Functional studies suggest that the variant may cause reduced protein expression compared to WT, however additional studies are needed to validate the impact of this variant on splicing (Howard et al., 2004); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32170002, 3239563, 25606380, 18409179, 25167861, 25326635, 20301622, 28293299, 33173999, 25679214, 26147798, 31685013, 29491882, 26997013, 20865721, 32277047, 26350204, 30231518, 36031702, 12953102, 28152038, 31452935, 24805811, 10632111, 15508018, 32901917, 15591283) (less)
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Pathogenic
(Jun 23, 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: SCV001582830.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
Studies have shown that this premature translational stop signal does not significantly alter or has an unclear effect on ATRX gene expression (PMID: 15508018, 15591283). … (more)
Studies have shown that this premature translational stop signal does not significantly alter or has an unclear effect on ATRX gene expression (PMID: 15508018, 15591283). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11742). This premature translational stop signal has been observed in individuals with clinical features of alpha-thalassemia X-linked intellectual disability syndrome (PMID: 10632111, 15508018, 24805811). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg37*) in the ATRX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATRX are known to be pathogenic (PMID: 15591283, 18409179, 23681356). (less)
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Pathogenic
(Dec 27, 2019)
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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: SCV002733914.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R37* pathogenic mutation (also known as c.109C>T), located in coding exon 2 of the ATRX gene, results from a C to T substitution at … (more)
The p.R37* pathogenic mutation (also known as c.109C>T), located in coding exon 2 of the ATRX gene, results from a C to T substitution at nucleotide position 109. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been shown to segregate with disease in several large families with variable intellectual disability (mild to profound), speech impairment, facial anomalies including +/- hypertelorism, short philtrum, open mouth, full lower lip, and microcephaly, growth deficiency, hypotonia, +/- seizures, +/- urogenital anomalies, and decreased Hgb H inclusions compared to most ATRX probands (Basehore MJ et al. Clin. Genet., 2015 May;87:461-6, Guerrini, R et al. Ann. Neurol. 2000;47(1):117-21, Moncini, S et al. Meta Gene 2013;1:102-108). This mutation is often observed to result in a less severe phenotype than is typically observed in patients with nonsense mutations in the ATRX gene, (Abidi, FE et al. Eur. J. Hum. Genet. 2005;13(2):176-83, Howard, MT et al. Med. Genet. 2004;41(12):951-6). Unaffected female carriers for this mutation have been observed to have highly skewed X-inactivation patterns of >90:10 (Abidi, FE et al. Eur. J. Hum. Genet. 2005;13(2):176-83, Basehore MJ et al. Clin. Genet., 2015 May;87:461-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Dec 01, 2004)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032742.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In 4 male cousins with the X-linked intellectual disability-hypotonic facies syndrome (MRXHF1; 309580), Guerrini et al. (2000) identified a 109C-T transition in exon 2 of … (more)
In 4 male cousins with the X-linked intellectual disability-hypotonic facies syndrome (MRXHF1; 309580), Guerrini et al. (2000) identified a 109C-T transition in exon 2 of the ATRX gene, resulting in an arg37-to-ter (R37X) substitution. Two patients had moderate to profound mental retardation and the typical facial features of the syndrome, whereas the other 2 patients presented with mild mental retardation and epilepsy, but without the characteristic facial dysmorphism. Howard et al. (2004) found that human embryonic kidney cells carrying the R37X mutation expressed approximately 20% of a slightly shortened ATRX protein compared to controls. Analysis of the 5-prime end of the ATRX gene revealed a downstream AUG start codon at residue 40, suggesting an alternative initiation event. Howard et al. (2004) suggested that 'phenotypic rescue' due to the expression of a truncated ATRX protein using the alternative downstream initiation site underlies the relatively mild phenotype seen in some patients with the R37X mutation. Abidi et al. (2005) identified the R37X mutation in 3 affected males originally reported by Chudley et al. (1988) as having Chudley-Lowry syndrome. Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against ATRX showed the protein to be present in lymphoblastoid cells, despite the premature stop codon. Abidi et al. (2005) suggested that the less severe phenotype was due to the presence of some residual ATRX protein. The phenotypic variation between patients with the same mutation suggested that the ATRX gene may influence the expression of several genes in multiple tissues during development. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Alpha thalassemia-X-linked intellectual disability syndrome
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000195529.2
First in ClinVar: Nov 25, 2014 Last updated: Oct 01, 2022 |
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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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Alpha-Thalassemia X-Linked Intellectual Disability Syndrome. | Adam MP | - | 2020 | PMID: 20301622 |
Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability. | Grozeva D | Human mutation | 2015 | PMID: 26350204 |
Alpha-thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation - c.109C>T (p.R37X). | Basehore MJ | Clinical genetics | 2015 | PMID: 24805811 |
Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. | Redin C | Journal of medical genetics | 2014 | PMID: 25167861 |
Neuroradiologic features in X-linked α-thalassemia/mental retardation syndrome. | Wada T | AJNR. American journal of neuroradiology | 2013 | PMID: 23681356 |
Mutations in the chromatin-associated protein ATRX. | Gibbons RJ | Human mutation | 2008 | PMID: 18409179 |
Mutation in the 5' alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome. | Abidi FE | European journal of human genetics : EJHG | 2005 | PMID: 15508018 |
Attenuation of an amino-terminal premature stop codon mutation in the ATRX gene by an alternative mode of translational initiation. | Howard MT | Journal of medical genetics | 2004 | PMID: 15591283 |
A nonsense mutation of the ATRX gene causing mild mental retardation and epilepsy. | Guerrini R | Annals of neurology | 2000 | PMID: 10632111 |
Carpenter-Waziri syndrome results from a mutation in XNP. | Abidi F | American journal of medical genetics | 1999 | PMID: 10398237 |
Mental retardation, distinct facial changes, short stature, obesity, and hypogonadism: a new X-linked mental retardation syndrome. | Chudley AE | American journal of medical genetics | 1988 | PMID: 3239563 |
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Text-mined citations for rs122445108 ...
HelpRecord last updated Sep 01, 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.