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

dbSNP: rs397518465

Total submissions: 10

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