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NM_007327.4(GRIN1):c.2381G>A (p.Arg794Gln) AND Intellectual disability, autosomal dominant 8

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Feb 25, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000500334.9

Allele description [Variation Report for NM_007327.4(GRIN1):c.2381G>A (p.Arg794Gln)]

NM_007327.4(GRIN1):c.2381G>A (p.Arg794Gln)

Gene:
GRIN1:glutamate ionotropic receptor NMDA type subunit 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9q34.3
Genomic location:
Preferred name:
NM_007327.4(GRIN1):c.2381G>A (p.Arg794Gln)
HGVS:
  • NC_000009.12:g.137163606G>A
  • NG_011507.1:g.29450G>A
  • NM_000832.7:c.2381G>A
  • NM_001185090.2:c.2444G>A
  • NM_001185091.2:c.2444G>A
  • NM_007327.4:c.2381G>AMANE SELECT
  • NM_021569.4:c.2381G>A
  • NP_000823.4:p.Arg794Gln
  • NP_001172019.1:p.Arg815Gln
  • NP_001172020.1:p.Arg815Gln
  • NP_015566.1:p.Arg794Gln
  • NP_067544.1:p.Arg794Gln
  • NC_000009.11:g.140058058G>A
  • NM_007327.3:c.2381G>A
Protein change:
R794Q
Links:
dbSNP: rs781053477
NCBI 1000 Genomes Browser:
rs781053477
Molecular consequence:
  • NM_000832.7:c.2381G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001185090.2:c.2444G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001185091.2:c.2444G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007327.4:c.2381G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021569.4:c.2381G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Intellectual disability, autosomal dominant 8 (NDHMSD)
Synonyms:
Mental retardation, autosomal dominant 8; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant
Identifiers:
MONDO: MONDO:0013655; MedGen: C3280282; OMIM: 614254

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000595058Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Dec 28, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000599265Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
no assertion criteria provided

(ACMG Guidelines, 2015)
Likely pathogenic
(Feb 2, 2016)
de novoclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003459883Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Feb 25, 2022)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.

Fry AE, Fawcett KA, Zelnik N, Yuan H, Thompson BAN, Shemer-Meiri L, Cushion TD, Mugalaasi H, Sims D, Stoodley N, Chung SK, Rees MI, Patel CV, Brueton LA, Layet V, Giuliano F, Kerr MP, Banne E, Meiner V, Lerman-Sagie T, Helbig KL, Kofman LH, et al.

Brain. 2018 Mar 1;141(3):698-712. doi: 10.1093/brain/awx358.

PubMed [citation]
PMID:
29365063
PMCID:
PMC5837214
See all PubMed Citations (3)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000595058.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV000599265.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV003459883.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GRIN1 function (PMID: 29365063). 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) performed at Invitae indicates that this missense variant is expected to disrupt GRIN1 protein function. ClinVar contains an entry for this variant (Variation ID: 435376). This missense change has been observed in individual(s) with clinical features of GRIN1-related conditions (PMID: 29365063). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 794 of the GRIN1 protein (p.Arg794Gln).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 20, 2024