Submissions for variant NM_007327.4(GRIN1):c.2530C>T (p.Arg844Cys)

dbSNP: rs1554770667

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623606	SCV000741889	pathogenic	Inborn genetic diseases	2016-10-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000730546	SCV000858291	likely pathogenic	not provided	2018-04-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763192	SCV000893804	likely pathogenic	Intellectual disability, autosomal dominant 8; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001043920	SCV001207689	pathogenic	Intellectual disability, autosomal dominant 8	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 844 of the GRIN1 protein (p.Arg844Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27159321, 27164704, 30776697). In at least one individual the variant was observed to be de novo. This variant is also known as c.2593C>T (p.Arg865Cys). ClinVar contains an entry for this variant (Variation ID: 521354). 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 GRIN1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GRIN1 function (PMID: 27164704). For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001043920	SCV001251875	likely pathogenic	Intellectual disability, autosomal dominant 8	2020-05-03	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260636	SCV001437728	likely pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000730546	SCV001766813	pathogenic	not provided	2022-12-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (increased and prolonged calcium influx in cortical neurons) (Furuse et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30776697, 27159321, 27164704, 20345915, 23688147, 30945278, 29124671)
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV001043920	SCV002525850	pathogenic	Intellectual disability, autosomal dominant 8	2022-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 865 of the GRIN1 protein (p.Arg865Cys), in exon 19. The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (Genome Aggregation Database). This variant has been previously reported in the literature related to the same phenotype as our patient (PMID: 27164704, 30776697, 30945278) and at the time ClinVar contains an entry with 8 pathogenic or likely pathogenic submissiones (Variation ID: 521354). This variant is also known as NM_007327.4:c.2530C>T;(p.Arg844Cys) in the literature. The variant is located in the Ca2+-calmodulin-binding domain, which is a well-established functional domain of the GRIN1 protein. In silico predictors (SIFT, Mutation Taster) suggest that this variant is likely to be disruptive and causative of disease. Therefore, there is sufficient evidence to classify the p.Arg865Cys variant as pathogenic for autosomal dominant GRIN1-associated neurodevelopmental disorder according to the ACMG guidelines (PS3, PM1, PM2, PP2, PP3, PP4).
Clinical Genomics Program, Stanford Medicine	RCV001043920	SCV001427060	pathogenic	Intellectual disability, autosomal dominant 8	2019-05-29	no assertion criteria provided	clinical testing	The p.Arg844Cys variant in the GRIN1 gene has been previously reported de novo in 4 individuals with features consistent with GRIN1-associated neurodevelopmental disorder (Lemke et al., 2016; Vanderver et al., 2016; Wang et al., 2019). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The GRIN1 gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that the p.Arg844Cys is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg844Cys variant as pathogenic for autosomal dominant GRIN1-associated neurodevelopmental disorder based on the information above. [ACMG evidence codes used: PS2_VeryStrong; PM2; PP2; PP3]