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NM_007327.4(GRIN1):c.2063C>A (p.Ser688Tyr) AND Intellectual disability, autosomal dominant 8

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 29, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002541569.5

Allele description [Variation Report for NM_007327.4(GRIN1):c.2063C>A (p.Ser688Tyr)]

NM_007327.4(GRIN1):c.2063C>A (p.Ser688Tyr)

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.2063C>A (p.Ser688Tyr)
HGVS:
  • NC_000009.12:g.137162895C>A
  • NG_011507.1:g.28739C>A
  • NM_000832.7:c.2063C>A
  • NM_001185090.2:c.2126C>A
  • NM_001185091.2:c.2126C>A
  • NM_007327.4:c.2063C>AMANE SELECT
  • NM_021569.4:c.2063C>A
  • NP_000823.4:p.Ser688Tyr
  • NP_001172019.1:p.Ser709Tyr
  • NP_001172020.1:p.Ser709Tyr
  • NP_015566.1:p.Ser688Tyr
  • NP_067544.1:p.Ser688Tyr
  • NC_000009.11:g.140057347C>A
  • NM_007327.3:c.2063C>A
Protein change:
S688Y
Links:
dbSNP: rs1833635820
NCBI 1000 Genomes Browser:
rs1833635820
Molecular consequence:
  • NM_000832.7:c.2063C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001185090.2:c.2126C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001185091.2:c.2126C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007327.4:c.2063C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_021569.4:c.2063C>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
Effect on ion channel function [Functional Epilepsy Nomenclature for Ion Channels: FENICS-0001]

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
SCV003441326Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Sep 29, 2022)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The pathogenic S688Y mutation in the ligand-binding domain of the GluN1 subunit regulates the properties of NMDA receptors.

Skrenkova K, Song JM, Kortus S, Kolcheva M, Netolicky J, Hemelikova K, Kaniakova M, Krausova BH, Kucera T, Korabecny J, Suh YH, Horak M.

Sci Rep. 2020 Oct 29;10(1):18576. doi: 10.1038/s41598-020-75646-w.

PubMed [citation]
PMID:
33122756
PMCID:
PMC7596085

De novo GRIN1 mutations: An emerging cause of severe early infantile encephalopathy.

Zehavi Y, Mandel H, Zehavi A, Rashid MA, Straussberg R, Jabur B, Shaag A, Elpeleg O, Spiegel R.

Eur J Med Genet. 2017 Jun;60(6):317-320. doi: 10.1016/j.ejmg.2017.04.001. Epub 2017 Apr 5.

PubMed [citation]
PMID:
28389307
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003441326.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 688 of the GRIN1 protein (p.Ser688Tyr). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GRIN1 function (PMID: 33122756). 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. ClinVar contains an entry for this variant (Variation ID: 981272). This missense change has been observed in individual(s) with clinical features of GRIN1-related conditions (PMID: 28389307). In at least one individual the variant was observed to be de novo.

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

Last Updated: Sep 29, 2024