NM_001134407.3(GRIN2A):c.2007+1G>T AND Landau-Kleffner syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Feb 13, 2021
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:: RCV001004716.8

Allele description [Variation Report for NM_001134407.3(GRIN2A):c.2007+1G>T]

NM_001134407.3(GRIN2A):c.2007+1G>T

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.2007+1G>T

HGVS:

NC_000016.10:g.9829422C>A
NG_011812.2:g.358333G>T
NM_000833.5:c.2007+1G>T
NM_001134407.3:c.2007+1G>TMANE SELECT
NM_001134408.2:c.2007+1G>T
NC_000016.9:g.9923279C>A
NC_000016.9:g.9923279C>A
NM_000833.3:c.2007+1G>T

Links:

Molecular consequence:

NM_000833.5:c.2007+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001134407.3:c.2007+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001134408.2:c.2007+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV001164181	Génétique des Maladies du Développement, Hospices Civils de Lyon	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 23, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002273655	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 13, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 23933819, 23933820, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001164181

Génétique des Maladies du Développement, Hospices Civils de Lyon

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 23, 2018)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002273655

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 13, 2021)

germline

clinical testing

PubMed (4)
[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
not provided	unknown	yes	not provided	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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (5)

Details of each submission

From Génétique des Maladies du Développement, Hospices Civils de Lyon, SCV001164181.1

#	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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002273655.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

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. Disruption of this splice site has been observed in individual(s) with GRIN2A-related conditions (PMID: 23933819). ClinVar contains an entry for this variant (Variation ID: 813774). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 10 of the GRIN2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GRIN2A are known to be pathogenic (PMID: 23933819, 23933820).

#	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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