NM_007327.4(GRIN1):c.2453T>G (p.Met818Arg) AND Intellectual disability, autosomal dominant 8

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 11, 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:: RCV002982849.3

Allele description [Variation Report for NM_007327.4(GRIN1):c.2453T>G (p.Met818Arg)]

NM_007327.4(GRIN1):c.2453T>G (p.Met818Arg)

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.2453T>G (p.Met818Arg)

HGVS:

NC_000009.12:g.137163768T>G
NG_011507.1:g.29612T>G
NM_000832.7:c.2453T>G
NM_001185090.2:c.2516T>G
NM_001185091.2:c.2516T>G
NM_007327.4:c.2453T>GMANE SELECT
NM_021569.4:c.2453T>G
NP_000823.4:p.Met818Arg
NP_001172019.1:p.Met839Arg
NP_001172020.1:p.Met839Arg
NP_015566.1:p.Met818Arg
NP_067544.1:p.Met818Arg
NC_000009.11:g.140058220T>G

Protein change:

M818R

Molecular consequence:

NM_000832.7:c.2453T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001185090.2:c.2516T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001185091.2:c.2516T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_007327.4:c.2453T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_021569.4:c.2453T>G - 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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connector enhancer of kinase suppressor of ras 3 [Mus musculus]
connector enhancer of kinase suppressor of ras 3 [Mus musculus]
gi|27369772|ref|NP_766134.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003295022	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 11, 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

SCV003295022

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 11, 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

Citations

PubMed

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003295022.2

#	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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Met818 amino acid residue in GRIN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. 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 methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 818 of the GRIN1 protein (p.Met818Arg).

#	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: Sep 29, 2024

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