NM_001134407.3(GRIN2A):c.2450T>C (p.Met817Thr) AND Landau-Kleffner syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 11, 2023
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:: RCV000989525.8

Allele description

NM_001134407.3(GRIN2A):c.2450T>C (p.Met817Thr)

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.2450T>C (p.Met817Thr)

HGVS:

NC_000016.10:g.9768996A>G
NG_011812.2:g.418759T>C
NM_000833.5:c.2450T>C
NM_001134407.3:c.2450T>CMANE SELECT
NM_001134408.2:c.2450T>C
NP_000824.1:p.Met817Thr
NP_001127879.1:p.Met817Thr
NP_001127880.1:p.Met817Thr
NC_000016.9:g.9862853A>G
NG_011812.1:g.418759T>C

Protein change:

M817T

Links:

dbSNP: rs1064796608

NCBI 1000 Genomes Browser:

rs1064796608

Molecular consequence:

NM_000833.5:c.2450T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001134407.3:c.2450T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001134408.2:c.2450T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

gain_of_function_variant [Sequence Ontology: SO:0002053]

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
SCV001139945	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001429992	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Mar 26, 2020)	de novo	clinical testing	Citation Link,
SCV002026156	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
SCV004539019	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28333917, 30544257, 28492532

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	1	not provided	not provided	1	not provided	clinical testing, research

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

A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.

Vissers LELM, van Nimwegen KJM, Schieving JH, Kamsteeg EJ, Kleefstra T, Yntema HG, Pfundt R, van der Wilt GJ, Krabbenborg L, Brunner HG, van der Burg S, Grutters J, Veltman JA, Willemsen MAAP.

Genet Med. 2017 Sep;19(9):1055-1063. doi: 10.1038/gim.2017.1. Epub 2017 Mar 23.

PubMed [citation]

PMID:: 28333917
PMCID:: PMC5589982

See all PubMed Citations (4)

Details of each submission

From Mendelics, SCV001139945.1

#	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 Munich, Klinikum Rechts Der Isar, TU München, SCV001429992.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002026156.1

#	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, SCV004539019.1

#	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 methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 817 of the GRIN2A protein (p.Met817Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GRIN2A-related conditions (PMID: 28333917, 30544257). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 803217). 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 GRIN2A protein function. For these reasons, this variant has been classified as Pathogenic.

#	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: Apr 20, 2024

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