NM_007327.4(GRIN1):c.2500G>C (p.Glu834Gln) AND Intellectual disability, autosomal dominant 8

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Sep 1, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000851520.12

Allele description [Variation Report for NM_007327.4(GRIN1):c.2500G>C (p.Glu834Gln)]

NM_007327.4(GRIN1):c.2500G>C (p.Glu834Gln)

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.2500G>C (p.Glu834Gln)

HGVS:

NC_000009.12:g.137163815G>C
NG_011507.1:g.29659G>C
NM_000832.7:c.2500G>C
NM_001185090.2:c.2563G>C
NM_001185091.2:c.2563G>C
NM_007327.4:c.2500G>CMANE SELECT
NM_021569.4:c.2500G>C
NP_000823.4:p.Glu834Gln
NP_001172019.1:p.Glu855Gln
NP_001172020.1:p.Glu855Gln
NP_015566.1:p.Glu834Gln
NP_067544.1:p.Glu834Gln
NC_000009.11:g.140058267G>C
NM_007327.3:c.2500G>C

Protein change:

E834Q

Links:

dbSNP: rs1588735834

NCBI 1000 Genomes Browser:

rs1588735834

Molecular consequence:

NM_000832.7:c.2500G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001185090.2:c.2563G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001185091.2:c.2563G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_007327.4:c.2500G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_021569.4:c.2500G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000994575	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 13, 2018)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001396681	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000994575

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 13, 2018)

de novo

clinical testing

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

SCV001396681

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 1, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical 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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, SCV000994575.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001396681.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 691274). This variant has not been reported in the literature in individuals affected with GRIN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 834 of the GRIN1 protein (p.Glu834Gln).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 19, 2025

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