ClinVar Miner

Submissions for variant NM_001134407.3(GRIN2A):c.1007+1G>A

dbSNP: rs397518465
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000726036 SCV000341369 pathogenic not provided 2016-06-03 criteria provided, single submitter clinical testing
Invitae RCV000074386 SCV000761171 pathogenic Landau-Kleffner syndrome 2023-08-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Landau-Kleffner syndrome, atypical benign partial epilepsy, benign epilepsy with centrotemporal spikes, and focal epilepsy (PMID: 23933818, 23933819, 28102150). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88727). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000726036 SCV001249506 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000074386 SCV002026172 likely pathogenic Landau-Kleffner syndrome 2019-01-01 criteria provided, single submitter research
GeneDx RCV000726036 SCV002043969 pathogenic not provided 2021-12-20 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28102150, 23933818, 7574460, 28832001, 29358611, 25921602, 31873310, 23933819)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000074386 SCV002767349 pathogenic Landau-Kleffner syndrome 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function, dominant negative and gain of function are known mechanisms of disease in this gene and are associated with focal epilepsy with speech disorder and with or without mental retardation (MIM#245570). Haploinsufficiency of GRIN2A is known to result in disease, and some variants have also been shown to act antagonistically to the wild type allele when two homologous subunits are incorporated into the same protein complex. Furthermore, the overall effect of these variants on complex activity results in a gain of function of the NMDA receptor (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Some carriers of familial variants are unaffected (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Disease presentation and severity is known to vary, even amongst family members carrying the same variant (OMIM). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another canonical splice site variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternate change to thymine at the same nucleotide has previously been reported in individuals with epilepsy (ClinVar, PMID: 23933819). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in more the five unrelated individuals with variable phenotypes on the epilepsy-aphasia spectrum (ClinVar, PMID: 23933819, PMID: 29124671). (SP) 0901 - This variant has strong evidence for segregation with disease. The variant has previously been shown to segregate with disease in at least two families (PMID: 23933819). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM RCV000074386 SCV000105996 pathogenic Landau-Kleffner syndrome 2013-09-01 no assertion criteria provided literature only
GeneReviews RCV000074386 SCV000320740 not provided Landau-Kleffner syndrome no assertion provided literature only
Bioinformatics Core, Luxembourg Center for Systems Biomedicine RCV000656049 SCV000588325 pathogenic Childhood epilepsy with centrotemporal spikes 2017-01-01 no assertion criteria provided case-control CAADphred>15
Diagnostic Laboratory, Strasbourg University Hospital RCV002274908 SCV002562802 likely pathogenic Abnormal cerebral morphology no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.