ClinVar Genomic variation as it relates to human health
NM_000827.4(GRIA1):c.1906G>A (p.Ala636Thr)
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_000827.4(GRIA1):c.1906G>A (p.Ala636Thr)
Variation ID: 39966 Accession: VCV000039966.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q33.2 5: 153764516 (GRCh38) [ NCBI UCSC ] 5: 153144076 (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, 2016 May 13, 2023 May 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000827.4:c.1906G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000818.2:p.Ala636Thr missense NM_001114183.2:c.1906G>A NP_001107655.1:p.Ala636Thr missense NM_001258019.2:c.1666G>A NP_001244948.1:p.Ala556Thr missense NM_001258020.2:c.1621G>A NP_001244949.1:p.Ala541Thr missense NM_001258021.2:c.1936G>A NP_001244950.1:p.Ala646Thr missense NM_001258022.2:c.1936G>A NP_001244951.1:p.Ala646Thr missense NM_001258023.1:c.1699G>A NP_001244952.1:p.Ala567Thr missense NM_001364165.2:c.1738G>A NP_001351094.1:p.Ala580Thr missense NM_001364166.2:c.1933G>A NP_001351095.1:p.Ala645Thr missense NM_001364167.2:c.1699G>A NP_001351096.1:p.Ala567Thr missense NR_047578.2:n.1987G>A non-coding transcript variant NR_157093.2:n.2125G>A non-coding transcript variant NC_000005.10:g.153764516G>A NC_000005.9:g.153144076G>A NG_047078.1:g.279821G>A - Protein change
- A636T, A556T, A645T, A646T, A541T, A567T, A580T
- Other names
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- Canonical SPDI
- NC_000005.10:153764515: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
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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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GRIA1 | - | - |
GRCh38 GRCh37 |
115 | 130 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2022 | RCV001269688.13 | |
Pathogenic (1) |
no assertion criteria provided
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May 17, 2021 | RCV001420360.8 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 11, 2023 | RCV002260601.10 |
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
Help
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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Likely pathogenic
(Jun 29, 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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449865.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Aug 16, 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: SCV001813284.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on channel desensitization (Taverna et al., 2000; Islail et al. 2022); Not observed at significant frequency in large … (more)
Published functional studies demonstrate a damaging effect on channel desensitization (Taverna et al., 2000; Islail et al. 2022); Not observed at significant frequency 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: 23033978, 28628100, 28191890, 31587869, 29220673, 31300657, 31785789, 20089915, 35887114, 35409220, Murtaza2022[functionalstudy], 35675825, 20048760, 10722683, 28714951) (less)
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Pathogenic
(Sep 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual developmental disorder, autosomal dominant 67
Affected status: yes
Allele origin:
de novo
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Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV003803869.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Sex: female
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Likely pathogenic
(May 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Intellectual developmental disorder, autosomal dominant 67
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV003924056.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Clinical Features:
Short attention span (present) , Delayed speech and language development (present) , Attention deficit hyperactivity disorder (present) , Cognitive impairment (present) , Impulsivity (present)
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Pathogenic
(Nov 15, 2012)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 67
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056881.5
First in ClinVar: Apr 04, 2013 Last updated: Jul 09, 2022 |
Comment on evidence:
In a girl (patient 2) with autosomal dominant intellectual developmental disorder-67 (MRD67; 619927), de Ligt et al. (2012) identified a heterozygous de novo c.1906G-A transition … (more)
In a girl (patient 2) with autosomal dominant intellectual developmental disorder-67 (MRD67; 619927), de Ligt et al. (2012) identified a heterozygous de novo c.1906G-A transition (c.1906G-A, NM_001114183.1) in the GRIA1 gene, resulting in an ala636-to-thr (A636T) substitution. Born after an uncomplicated pregnancy and delivery, she showed global developmental delay with impaired intellectual development and no speech. Brain imaging was normal; she did not have seizures. Functional studies of the variant were not performed. Geisheker et al. (2017) identified a recurrent heterozygous A636T mutation in the GRIA1 gene in 3 unrelated patients with MRD67. The mutation was demonstrated to occur de novo in 1 patient; paternal DNA was not available for the other 2 patients, but the mutation was not present in either mother. The mutation, which occurred within a highly conserved region in the M3 transmembrane domain, was not present in the ExAC database. In vitro functional expression studies in HEK293 cells transfected with the mutation showed presence of a constitutive current, consistent with a gain-of-function effect, although a dominant effect of the mutation was not observed when cotransfected with wildtype GRIA1. The authors suggested that the mutation may cause a defect in early synaptic development. Phenotypic information from 4 patients with the mutation (including the patient reported by de Ligt et al., 2012) showed that all had autism spectrum disorder (ASD) and mild to moderate intellectual disability with variable speech delay and other behavioral abnormalities, including ADHD, OCD, and motor tics. One patient had seizures between ages 2 and 5. The study of Geisheker et al. (2017) included a large cohort of over 17,000 patients with a diagnosis of ASD or developmental delay who underwent genetic studies. Geisheker et al. (2017) noted that De Rubeis et al. (2014) had identified a de novo A636T mutation in a patient from a large cohort of patients with ASD who underwent exome sequencing. Clinical details were not provided. Ismail et al. (2022) identified a de novo heterozygous A636T mutation in 2 unrelated patients (P3 and P4) with MRD67. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Xenopus oocytes expressing the A636T mutation showed a 10-fold increased current, impaired desensitization, increased sensitivity towards glu, and increased channel-opening ability compared to controls. These findings were consistent with a gain-of-function effect. (less)
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Pathogenic
(May 17, 2021)
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no assertion criteria provided
Method: clinical testing
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Intellectual disability
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Service de Biochimie Médicale et Biologie Moléculaire, CHU Clermont-Ferrand
Accession: SCV001622437.1
First in ClinVar: May 20, 2021 Last updated: May 20, 2021 |
Comment:
PS2 + PS3 + PM2 + PP3
Clinical Features:
Global developmental delay (present) , Delayed speech and language development (present)
Age: 0-9 years
Sex: male
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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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Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome. | Ismail V | American journal of human genetics | 2022 | PMID: 35675825 |
Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. | Geisheker MR | Nature neuroscience | 2017 | PMID: 28628100 |
Synaptic, transcriptional and chromatin genes disrupted in autism. | De Rubeis S | Nature | 2014 | PMID: 25363760 |
Diagnostic exome sequencing in persons with severe intellectual disability. | de Ligt J | The New England journal of medicine | 2012 | PMID: 23033978 |
Text-mined citations for rs587776937 ...
HelpRecord last updated Apr 20, 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.