ClinVar Genomic variation as it relates to human health
NM_007327.4(GRIN1):c.1858G>C (p.Gly620Arg)
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_007327.4(GRIN1):c.1858G>C (p.Gly620Arg)
Variation ID: 209159 Accession: VCV000209159.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.3 9: 137162510 (GRCh38) [ NCBI UCSC ] 9: 140056962 (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 Sep 29, 2015 Oct 8, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007327.4:c.1858G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_015566.1:p.Gly620Arg missense NM_000832.7:c.1858G>C NP_000823.4:p.Gly620Arg missense NM_001185090.2:c.1921G>C NP_001172019.1:p.Gly641Arg missense NM_001185091.2:c.1921G>C NP_001172020.1:p.Gly641Arg missense NM_021569.4:c.1858G>C NP_067544.1:p.Gly620Arg missense NC_000009.12:g.137162510G>C NC_000009.11:g.140056962G>C NG_011507.1:g.28354G>C - Protein change
- G620R, G641R
- Other names
- GRIN1, GLY620ARG, 1858G-C
- Canonical SPDI
- NC_000009.12:137162509:G: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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GRIN1 | - | - |
GRCh38 GRCh37 |
1026 | 1126 |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV000191091.14 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 21, 2023 | RCV000479068.25 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 24, 2018 | RCV000622498.4 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001526577.3 |
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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Likely pathogenic
(Oct 21, 2014)
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criteria provided, single submitter
Method: clinical testing
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Mental retardation, autosomal dominant 8
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Study: Adult_WES
Accession: SCV000245488.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment:
Likely pathogenicity based on finding it twice in our laboratory de novo: in a 24-year-old female with absent speech, autism, intellectual disability, mild unilateral conductive … (more)
Likely pathogenicity based on finding it twice in our laboratory de novo: in a 24-year-old female with absent speech, autism, intellectual disability, mild unilateral conductive hearing loss, spasticity, joint laxity, failure to thrive, gastroesophageal disorder, strabismus, myopia, mild mitral valve prolapse, intermittent episodes of syncope, and scoliosis; in a 7-year-old male with absent speech, regression, intellectual disability, congenital hypotonia, movement disorder, short stature (less)
Number of individuals with the variant: 2
Age: 7-24 years
Sex: mixed
Ethnicity/Population group: Causasians
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Seizure
Affected status: yes
Allele origin:
de novo
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737004.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
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Pathogenic
(Jan 19, 2021)
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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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002051694.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022 |
Comment:
PS3, PP2, PP3, PM1, PM2, PS4_Moderate
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Pathogenic
(Apr 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal dominant 8
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511789.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: GRIN1 c.1858G>C (p.Gly620Arg) results in a non-conservative amino acid change located in the Ionotropic glutamate receptor domain (IPR001320) of the encoded protein sequence. … (more)
Variant summary: GRIN1 c.1858G>C (p.Gly620Arg) results in a non-conservative amino acid change located in the Ionotropic glutamate receptor domain (IPR001320) 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 244402 control chromosomes. c.1858G>C has been reported in the literature as a de-novo variant in multiple individuals affected with features of Autosomal Dominant Neurodevelopmental Disorder With Or Without Hyperkinetic Movements And Seizures (example, Chen_2017, Lemke_2016, Costain_2019, Li_2019, Santos-Gomez_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting a reduction in N-methyl-D-aspartate (NMDAR) receptor trafficking, expression and function (example, Chen_2017). 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 21, 2023)
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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: SCV000569832.5
First in ClinVar: Apr 27, 2017 Last updated: Feb 07, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: loss of NMDA receptor function (Lemke et al., 2016; Chen et al., 2017); Not observed at significant frequency … (more)
Published functional studies demonstrate a damaging effect: loss of NMDA receptor function (Lemke et al., 2016; Chen et al., 2017); 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: 27164704, 26633545, 28228639, 31487502, 31429998) (less)
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, autosomal dominant 8
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002240115.4
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 620 of the GRIN1 protein (p.Gly620Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 620 of the GRIN1 protein (p.Gly620Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant GRIN1-related conditions (PMID: 28228639, 34884460). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 209159). 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 GRIN1 protein function. Experimental studies have shown that this missense change affects GRIN1 function (PMID: 28228639, 31429998). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 24, 2018)
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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: SCV000742522.4
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The p.G620R variant (also known as c.1858G>C), located in coding exon 13 of the GRIN1 gene, results from a G to C substitution at nucleotide … (more)
The p.G620R variant (also known as c.1858G>C), located in coding exon 13 of the GRIN1 gene, results from a G to C substitution at nucleotide position 1858. The glycine at codon 620 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in individuals with intellectual disability and has been shown to have an impact on protein function (Lemke JR et al. Neurology, 2016 06;86:2171-8; Chen W et al. J. Hum. Genet., 2017 Jun;62:589-597). In addition, this variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with global developmental delay and hypotonia (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Mar 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002498081.17
First in ClinVar: Apr 08, 2022 Last updated: Oct 08, 2024 |
Comment:
GRIN1: PS2, PM1, PM2, PP2, PP3, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Mar 28, 2022)
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no assertion criteria provided
Method: literature only
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NEURODEVELOPMENTAL DISORDER WITH HYPERKINETIC MOVEMENTS AND WITHOUT SEIZURES, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000678284.3
First in ClinVar: Jan 13, 2018 Last updated: Apr 02, 2022 |
Comment on evidence:
In a 25-year-old woman (proband 2) with autosomal dominant neurodevelopmental disorder with hyperkinetic movements without seizures (NDHMSD; 614254), Chen et al. (2017) identified a de … (more)
In a 25-year-old woman (proband 2) with autosomal dominant neurodevelopmental disorder with hyperkinetic movements without seizures (NDHMSD; 614254), Chen et al. (2017) identified a de novo heterozygous c.1858G-C transversion in exon 13 of the GRIN1 gene, resulting in a G620R substitution. Chen et al. (2017) noted that the G620R substitution resulting from a c.1858G-C transversion had been identified by Lemke et al. (2016) in a 7-year-old boy (patient 9) with a similar phenotype. Chen et al. (2017) found the same G620R substitution but resulting from a different nucleotide change in an unrelated boy with the disorder (138249.0011). (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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Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum. | Santos-Gómez A | International journal of molecular sciences | 2021 | PMID: 34884460 |
Clinical Application of Targeted Next-Generation Sequencing Panels and Whole Exome Sequencing in Childhood Epilepsy. | Costain G | Neuroscience | 2019 | PMID: 31487502 |
De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases. | Li J | Human mutation | 2019 | PMID: 31429998 |
GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function. | Chen W | Journal of human genetics | 2017 | PMID: 28228639 |
Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy. | Lemke JR | Neurology | 2016 | PMID: 27164704 |
Molecular diagnostic experience of whole-exome sequencing in adult patients. | Posey JE | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26633545 |
Text-mined citations for rs797045047 ...
HelpRecord last updated Oct 08, 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.