ClinVar Genomic variation as it relates to human health
NM_181672.3(OGT):c.1942A>T (p.Asn648Tyr)
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_181672.3(OGT):c.1942A>T (p.Asn648Tyr)
Variation ID: 691611 Accession: VCV000691611.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq13.1 X: 71561865 (GRCh38) [ NCBI UCSC ] X: 70781715 (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 Oct 10, 2019 Oct 1, 2022 May 29, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_181672.3(OGT):c.1942A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_181672.3:c.1942A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_858058.1:p.Asn648Tyr missense NM_181673.3:c.1912A>T NP_858059.1:p.Asn638Tyr missense NC_000023.11:g.71561865A>T NC_000023.10:g.70781715A>T NG_015875.1:g.33804A>T - Protein change
- N638Y, N648Y
- Other names
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- Canonical SPDI
- NC_000023.11:71561864:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on catalytic protein function Variation Ontology [VariO:0008]
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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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OGT | - | - |
GRCh38 GRCh37 |
118 | 244 |
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 (3) |
criteria provided, single submitter
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May 29, 2020 | RCV000852378.4 |
Submissions - Germline
Classification
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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
(May 29, 2020)
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criteria provided, single submitter
Method: research
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Intellectual disability, X-linked 106
(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: SCV001430738.1
First in ClinVar: Aug 23, 2020 Last updated: Aug 23, 2020 |
Comment:
The hemizygous p.Asn648Tyr variant in OGT was identified by our study in 1 individual with x-linked intellectual disability (PMID: 31627256). Trio genome analysis showed this … (more)
The hemizygous p.Asn648Tyr variant in OGT was identified by our study in 1 individual with x-linked intellectual disability (PMID: 31627256). Trio genome analysis showed this variant to be de novo, and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID#: 691611) as pathogenic by Daan van Aalten Lab,University of Dundee. In vitro functional studies provide some evidence that the p.Asn648Tyr variant may slightly impact protein function (PMID: 31627256). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Asn648Tyr variant is located in a region of OGT that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 31627256). The number of missense variants reported in OGT 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. Furthermore, although this gene has been reported in association with x-linked intellectual disability, it currently has limited/moderate evidence for these associations. In summary, this variant meets criteria to be classified as pathogenic for x-linked intellectual disability in an autosomal recessive manner based on an individual with the disease and a de novo variant in this gene, absence of this variant from the general population, and functional assays showing disruption to protein function in vitro. ACMG/AMP Criteria applied: PS2, PM2, PP3, PS3_supporting (Richards 2015). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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MENTAL RETARDATION, X-LINKED 106
Affected status: yes
Allele origin:
de novo
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Daan van Aalten Lab, University of Dundee
Accession: SCV000992606.1
First in ClinVar: Oct 10, 2019 Last updated: Oct 10, 2019 |
Indication for testing: Clinical features observed in this individual
Sex: male
Comment on evidence:
Trio whole genome sequencing was performed. After variant filtration for de novo, recessive or X-linked variants with allele frequencies below 1%, we identified a missense … (more)
Trio whole genome sequencing was performed. After variant filtration for de novo, recessive or X-linked variants with allele frequencies below 1%, we identified a missense variant in the OGT gene ChrX (GRCh38): g.71561865A>T; NM_181672.2: c.1942A>T p.(Asn648Tyr). Both parents and sibling were healthy and did not carry this mutation. (less)
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Pathogenic
(Sep 25, 2022)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 106
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV002576386.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment on evidence:
In a boy with X-linked intellectual developmental disorder-106 (XLID106; 300997), Pravata et al. (2020) identified a hemizygous c.1942A-T transversion (c.1942A-T, NM_181672.2) in the OGT gene, … (more)
In a boy with X-linked intellectual developmental disorder-106 (XLID106; 300997), Pravata et al. (2020) identified a hemizygous c.1942A-T transversion (c.1942A-T, NM_181672.2) in the OGT gene, resulting in an asn648-to-tyr (N648Y) substitution at a conserved residue in the catalytic domain. The mutation, which was identified by trio whole-exome sequencing, was shown to be de novo. Recombinant OGT protein with the N648Y mutation demonstrated reduced substrate binding compared to wildtype and reduced glycosylation of a model acceptor substrate, TAB1. (less)
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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effect on catalytic protein function
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Daan van Aalten Lab, University of Dundee
Accession: SCV000992606.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A missense mutation in the catalytic domain of O-GlcNAc transferase links perturbations in protein O-GlcNAcylation to X-linked intellectual disability. | Pravata VM | FEBS letters | 2020 | PMID: 31627256 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/e90e2998-7fc3-4a6e-8ccf-7ffe7099069b | - | - | - | - |
Text-mined citations for rs1602152230 ...
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.