NM_001134407.3(GRIN2A):c.1904C>A (p.Ala635Asp) AND Landau-Kleffner syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Feb 3, 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:: RCV001202493.9

Allele description [Variation Report for NM_001134407.3(GRIN2A):c.1904C>A (p.Ala635Asp)]

NM_001134407.3(GRIN2A):c.1904C>A (p.Ala635Asp)

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.1904C>A (p.Ala635Asp)

HGVS:

NC_000016.10:g.9829526G>T
NG_011812.2:g.358229C>A
NM_000833.5:c.1904C>A
NM_001134407.3:c.1904C>AMANE SELECT
NM_001134408.2:c.1904C>A
NP_000824.1:p.Ala635Asp
NP_001127879.1:p.Ala635Asp
NP_001127880.1:p.Ala635Asp
NC_000016.9:g.9923383G>T
NG_011812.1:g.358229C>A
NM_000833.3:c.1904C>A
NM_000833.4:c.1904C>A

Protein change:

A635D

Links:

dbSNP: rs2042448930

NCBI 1000 Genomes Browser:

rs2042448930

Molecular consequence:

NM_000833.5:c.1904C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001134407.3:c.1904C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001134408.2:c.1904C>A - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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Homo sapiens chromosome 11, GRCh38.p14 Primary Assembly
Homo sapiens chromosome 11, GRCh38.p14 Primary Assembly
gi|568815587|gnl|ASM:GCF_000001305| f|NC_000011.10||gpp|GPC_000001303.1||gnl|NCBI_GENOMES|11

Nucleotide
Homo sapiens ceramide kinase like (CERKL), transcript variant 3, mRNA
Homo sapiens ceramide kinase like (CERKL), transcript variant 3, mRNA
gi|1890271534|ref|NM_001030312.3|

Nucleotide
Structure Links for Protein (Select 1443492550) (7)
Structure
Microbe sample from Vibrio lentus
Microbe sample from Vibrio lentus

biosample
Bac*Drom
Bac*Drom

biosample

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001373606	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 3, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30544257, 33258288, 28492532
SCV002505718	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 1, 2021)	de novo	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

SCV001373606

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 3, 2022)

germline

clinical testing

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

SCV002505718

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 1, 2021)

de novo

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	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.

Quaio CRDC, Moreira CM, Novo-Filho GM, Sacramento-Bobotis PR, Groenner Penna M, Perazzio SF, Dutra AP, da Silva RA, Santos MNP, de Arruda VYN, Freitas VG, Pereira VC, Pintao MC, Fornari ARDS, Buzolin AL, Oku AY, Burger M, Ramalho RF, Marco Antonio DS, E Ferreira EN, Pereira OJE, Cantagalli VD, et al.

Am J Med Genet C Semin Med Genet. 2020 Dec;184(4):955-964. doi: 10.1002/ajmg.c.31860. Epub 2020 Nov 30.

PubMed [citation]

PMID:: 33258288

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001373606.5

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

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.Ala635 amino acid residue in GRIN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30544257, 33258288). 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 GRIN2A protein function. ClinVar contains an entry for this variant (Variation ID: 934152). This variant has not been reported in the literature in individuals affected with GRIN2A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 635 of the GRIN2A protein (p.Ala635Asp).

#	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

From Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, SCV002505718.2

#	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

Last Updated: Feb 20, 2024

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