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NM_007327.4(GRIN1):c.2449T>C (p.Phe817Leu) AND Intellectual disability, autosomal dominant 8

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 28, 2022
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV000576887.4

Allele description [Variation Report for NM_007327.4(GRIN1):c.2449T>C (p.Phe817Leu)]

NM_007327.4(GRIN1):c.2449T>C (p.Phe817Leu)

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.2449T>C (p.Phe817Leu)
HGVS:
  • NC_000009.12:g.137163764T>C
  • NG_011507.1:g.29608T>C
  • NM_000832.7:c.2449T>C
  • NM_001185090.2:c.2512T>C
  • NM_001185091.2:c.2512T>C
  • NM_007327.4:c.2449T>CMANE SELECT
  • NM_021569.4:c.2449T>C
  • NP_000823.4:p.Phe817Leu
  • NP_001172019.1:p.Phe838Leu
  • NP_001172020.1:p.Phe838Leu
  • NP_015566.1:p.Phe817Leu
  • NP_067544.1:p.Phe817Leu
  • NC_000009.11:g.140058216T>C
  • NM_007327.3:c.2449T>C
Protein change:
F817L; PHE817LEU
Links:
OMIM: 138249.0007; dbSNP: rs1554770624
NCBI 1000 Genomes Browser:
rs1554770624
Molecular consequence:
  • NM_000832.7:c.2449T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001185090.2:c.2512T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001185091.2:c.2512T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007327.4:c.2449T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021569.4:c.2449T>C - 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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000678279OMIM
no assertion criteria provided
Pathogenic
(Mar 28, 2022) 		germlineliterature only

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy.

Lemke JR, Geider K, Helbig KL, Heyne HO, Schütz H, Hentschel J, Courage C, Depienne C, Nava C, Heron D, Møller RS, Hjalgrim H, Lal D, Neubauer BA, Nürnberg P, Thiele H, Kurlemann G, Arnold GL, Bhambhani V, Bartholdi D, Pedurupillay CR, Misceo D, et al.

Neurology. 2016 Jun 7;86(23):2171-8. doi: 10.1212/WNL.0000000000002740. Epub 2016 May 6.

PubMed [citation]
PMID:
27164704
PMCID:
PMC4898312

Details of each submission

From OMIM, SCV000678279.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 2 unrelated patients (patients 19 and 20) with autosomal dominant neurodevelopmental disorder with hyperkinetic movements and without seizures (NDHMSD; 614254), Lemke et al. (2016) identified a de novo heterozygous c.2449T-C transition (c.2449T-C, NM_007327) in the GRIN1 gene, resulting in a phe817-to-leu (F817L) substitution at a conserved residue in the M4 domain. The mutations were found by next-generation sequencing approaches and confirmed by Sanger sequencing; patient 20 had previously been reported. In vitro functional expression studies in Xenopus oocytes showed that the mutation resulted in a partial loss of receptor function, with decreased affinity for glutamate and glycine; studies showed a dominant-negative effect of the F817L mutant when coexpressed with wildtype GRIN2B (138252). Molecular modeling predicted that the mutation would destabilize the assembly of NMDAR.

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

Last Updated: Aug 5, 2023