9-137163845-C-T

Variant names:

• chr9-137163845-C-T
• rs1554770667
• NM_007327.4:c.2530C>T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP2 PP5_Very_Strong

The NM_007327.4(GRIN1):​c.2530C>T​(p.Arg844Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R844P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.51

Genes affected

GRIN1 (HGNC:4584): (glutamate ionotropic receptor NMDA type subunit 1) The protein encoded by this gene is a critical subunit of N-methyl-D-aspartate receptors, members of the glutamate receptor channel superfamily which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits play a key role in the plasticity of synapses, which is believed to underlie memory and learning. Cell-specific factors are thought to control expression of different isoforms, possibly contributing to the functional diversity of the subunits. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-137163846-G-C is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in the GRIN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 75 curated pathogenic missense variants (we use a threshold of 10). The gene has 49 curated benign missense variants. Gene score misZ: 6.2157 (above the threshold of 3.09). Trascript score misZ: 6.6419 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy 101, neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive, autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 8.
• PP5: Variant 9-137163845-C-T is Pathogenic according to our data. Variant chr9-137163845-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137163845-C-T is described in Lovd as [Likely_pathogenic]. Variant chr9-137163845-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.2530C>T	p.Arg844Cys	missense_variant	Exon 18 of 20	ENST00000371561.8	NP_015566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8	c.2530C>T	p.Arg844Cys	missense_variant	Exon 18 of 20	1	NM_007327.4	ENSP00000360616.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 8 Pathogenic:4

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2022

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

May 29, 2019

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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] -

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GRIN1 protein function with a positive predictive value of 95%. 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. -

not provided Pathogenic:2

Apr 23, 2018

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Intellectual disability, autosomal dominant 8;C4693325:Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Oct 14, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability Pathogenic:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;.;T;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.0017	T
MutationAssessor	Benign	1.1	L;L;.;.;.;L;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D;.
Vest4		0.37
MutPred		0.77		Loss of disorder (P = 0.0076);Loss of disorder (P = 0.0076);.;.;.;Loss of disorder (P = 0.0076);.;
MVP		0.84
MPC		3.0
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.83
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554770667; hg19: chr9-140058297;