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NM_001134407.3(GRIN2A):c.2095C>A (p.Pro699Thr) AND Landau-Kleffner syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 17, 2024
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:
RCV003582368.2

Allele description [Variation Report for NM_001134407.3(GRIN2A):c.2095C>A (p.Pro699Thr)]

NM_001134407.3(GRIN2A):c.2095C>A (p.Pro699Thr)

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.2095C>A (p.Pro699Thr)
HGVS:
  • NC_000016.10:g.9822337G>T
  • NG_011812.2:g.365418C>A
  • NM_000833.5:c.2095C>A
  • NM_001134407.3:c.2095C>AMANE SELECT
  • NM_001134408.2:c.2095C>A
  • NP_000824.1:p.Pro699Thr
  • NP_001127879.1:p.Pro699Thr
  • NP_001127880.1:p.Pro699Thr
  • NC_000016.9:g.9916194G>T
Protein change:
P699T
Molecular consequence:
  • NM_000833.5:c.2095C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001134407.3:c.2095C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001134408.2:c.2095C>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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004260780Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 17, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.

Lemke JR, Lal D, Reinthaler EM, Steiner I, Nothnagel M, Alber M, Geider K, Laube B, Schwake M, Finsterwalder K, Franke A, Schilhabel M, Jähn JA, Muhle H, Boor R, Van Paesschen W, Caraballo R, Fejerman N, Weckhuysen S, De Jonghe P, Larsen J, Møller RS, et al.

Nat Genet. 2013 Sep;45(9):1067-72. doi: 10.1038/ng.2728. Epub 2013 Aug 11.

PubMed [citation]
PMID:
23933819

Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.

Swanger SA, Chen W, Wells G, Burger PB, Tankovic A, Bhattacharya S, Strong KL, Hu C, Kusumoto H, Zhang J, Adams DR, Millichap JJ, Petrovski S, Traynelis SF, Yuan H.

Am J Hum Genet. 2016 Dec 1;99(6):1261-1280. doi: 10.1016/j.ajhg.2016.10.002. Epub 2016 Nov 10.

PubMed [citation]
PMID:
27839871
PMCID:
PMC5142120
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004260780.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 699 of the GRIN2A protein (p.Pro699Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GRIN2A-related conditions. 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. This variant disrupts the p.Pro699 amino acid residue in GRIN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23933819, 27839871). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024