NM_000834.5(GRIN2B):c.1831G>C (p.Gly611Arg) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 25, 2021
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:: RCV002008382.6

Allele description [Variation Report for NM_000834.5(GRIN2B):c.1831G>C (p.Gly611Arg)]

NM_000834.5(GRIN2B):c.1831G>C (p.Gly611Arg)

Gene:

GRIN2B:glutamate ionotropic receptor NMDA type subunit 2B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p13.1

Genomic location:

Preferred name:

NM_000834.5(GRIN2B):c.1831G>C (p.Gly611Arg)

HGVS:

NC_000012.12:g.13608782C>G
NG_031854.2:g.378231G>C
NM_000834.5:c.1831G>CMANE SELECT
NP_000825.2:p.Gly611Arg
NC_000012.11:g.13761716C>G

Protein change:

G611R

Links:

dbSNP: rs2136470509

NCBI 1000 Genomes Browser:

rs2136470509

Molecular consequence:

NM_000834.5:c.1831G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Intellectual disability, autosomal dominant 6 (MRD6)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6, WITH OR WITHOUT SEIZURES
Identifiers:: MONDO: MONDO:0013509; MedGen: C3151411; OMIM: 613970

Name:: Developmental and epileptic encephalopathy, 27 (DEE27)
Synonyms:: Epileptic encephalopathy, early infantile, 27
Identifiers:: MONDO: MONDO:0014505; MedGen: C4015316; Orphanet: 3451; OMIM: 616139

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002268056	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 25, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28377535, 31429998, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002268056

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 25, 2021)

germline

clinical testing

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

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

GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.

Platzer K, Yuan H, Schütz H, Winschel A, Chen W, Hu C, Kusumoto H, Heyne HO, Helbig KL, Tang S, Willing MC, Tinkle BT, Adams DJ, Depienne C, Keren B, Mignot C, Frengen E, Strømme P, Biskup S, Döcker D, Strom TM, Mefford HC, et al.

J Med Genet. 2017 Jul;54(7):460-470. doi: 10.1136/jmedgenet-2016-104509. Epub 2017 Apr 4.

PubMed [citation]

PMID:: 28377535
PMCID:: PMC5656050

De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases.

Li J, Zhang J, Tang W, Mizu RK, Kusumoto H, XiangWei W, Xu Y, Chen W, Amin JB, Hu C, Kannan V, Keller SR, Wilcox WR, Lemke JR, Myers SJ, Swanger SA, Wollmuth LP, Petrovski S, Traynelis SF, Yuan H.

Hum Mutat. 2019 Dec;40(12):2393-2413. doi: 10.1002/humu.23895. Epub 2019 Sep 10.

PubMed [citation]

PMID:: 31429998
PMCID:: PMC6874887

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002268056.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glycine with arginine at codon 611 of the GRIN2B protein (p.Gly611Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). 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.Gly611 amino acid residue in GRIN2B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28377535, 31429998). 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 GRIN2B protein function. This variant has been observed in individual(s) with clinical features of GRIN2B-related conditions (Invitae).

#	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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