NM_001134407.3(GRIN2A):c.2453C>A (p.Ala818Glu) AND Landau-Kleffner syndrome

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jun 26, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000585832.5

Allele description [Variation Report for NM_001134407.3(GRIN2A):c.2453C>A (p.Ala818Glu)]

NM_001134407.3(GRIN2A):c.2453C>A (p.Ala818Glu)

Gene:

GRIN2A:glutamate ionotropic receptor NMDA type subunit 2A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.2

Genomic location:

Preferred name:

NM_001134407.3(GRIN2A):c.2453C>A (p.Ala818Glu)

Other names:

C2453A

HGVS:

NC_000016.10:g.9768993G>T
NG_011812.2:g.418762C>A
NM_000833.5:c.2453C>A
NM_001134407.3:c.2453C>AMANE SELECT
NM_001134408.2:c.2453C>A
NP_000824.1:p.Ala818Glu
NP_001127879.1:p.Ala818Glu
NP_001127880.1:p.Ala818Glu
NC_000016.9:g.9862850G>T
NG_011812.1:g.418762C>A
NM_000833.4:c.2453C>A

Protein change:

A818E

Links:

dbSNP: rs751455326

NCBI 1000 Genomes Browser:

rs751455326

Molecular consequence:

NM_000833.5:c.2453C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001134407.3:c.2453C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001134408.2:c.2453C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Landau-Kleffner syndrome (FESD)
Synonyms:: Acquired aphasia with convulsive disorder; Acquired epileptiform aphasia; APHASIA, ACQUIRED, WITH EPILEPSY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009509; MedGen: C0282512; Orphanet: 1945; Orphanet: 725; Orphanet: 98818; OMIM: 245570

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000622118	Ambulatório de Genética Médica, Hospital Escola da Universidade Federal de Pelotas	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 20, 2017)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001139944	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV002026159	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2019)	de novo	research	PubMed (2) [See all records that cite these PMIDs] 30544257, 25741868
SCV003484106	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 26, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30544257, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Caucasian	de novo	yes	1	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

Strehlow V, Heyne HO, Vlaskamp DRM, Marwick KFM, Rudolf G, de Bellescize J, Biskup S, Brilstra EH, Brouwer OF, Callenbach PMC, Hentschel J, Hirsch E, Kind PC, Mignot C, Platzer K, Rump P, Skehel PA, Wyllie DJA, Hardingham GE, van Ravenswaaij-Arts CMA, Lesca G, Lemke JR; et al.

Brain. 2019 Jan 1;142(1):80-92. doi: 10.1093/brain/awy304.

PubMed [citation]

PMID:: 30544257
PMCID:: PMC6308310

See all PubMed Citations (3)

Details of each submission

From Ambulatório de Genética Médica, Hospital Escola da Universidade Federal de Pelotas, SCV000622118.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	clinical testing (GTR000509909.1)	PubMed (1)

Description

Patient with this de novo variant (parents tested) shows the compatible clinical phenotype, including epilepsy and developmental delay.

#	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	(GTR000509909.1)	1	not provided	not provided	not provided

From Mendelics, SCV001139944.1

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

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002026159.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

#	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 Invitae, SCV003484106.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. 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 GRIN2A protein function. ClinVar contains an entry for this variant (Variation ID: 495226). This missense change has been observed in individual(s) with GRIN2A related disorders (PMID: 30544257). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 818 of the GRIN2A protein (p.Ala818Glu).

#	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: Feb 20, 2024

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