rs1554770667

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-137163845-C-T
• chr9-137163845-C-A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PM5 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 (★★). ClinVar reports functional evidence for this variant: "SCV000741889: Functional studies suggest that the p.R844C alteration produced functional NMDA receptors with agonist Imax values and glycine affinity similar to wild-type receptors and therefore, that this alteration may impact NMDA receptor function through other mechanisms" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R844L) 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:12
• Conservation: PhyloP100: 4.51
• Publications: 0 publications found

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]

GRIN1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
• developmental and epileptic encephalopathy 101

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000741889: Functional studies suggest that the p.R844C alteration produced functional NMDA receptors with agonist Imax values and glycine affinity similar to wild-type receptors and therefore, that this alteration may impact NMDA receptor function through other mechanisms; however, additional evidence is needed to confirm these findings (Lemke, 2016).; SCV001766813: Published functional studies demonstrate a damaging effect (increased and prolonged calcium influx in cortical neurons) (Furuse et al., 2010)
• 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-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 598966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 9-137163845-C-T is Pathogenic according to our data. Variant chr9-137163845-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007327.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	NM_007327.4	MANE Select	c.2530C>T	p.Arg844Cys	missense	Exon 18 of 20	NP_015566.1	Q05586-1
	GRIN1	NM_001437330.1		c.2593C>T	p.Arg865Cys	missense	Exon 19 of 21	NP_001424259.1
	GRIN1	NM_001185090.2		c.2593C>T	p.Arg865Cys	missense	Exon 19 of 21	NP_001172019.1	Q05586-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	ENST00000371561.8	TSL:1 MANE Select	c.2530C>T	p.Arg844Cys	missense	Exon 18 of 20	ENSP00000360616.3	Q05586-1
	GRIN1	ENST00000371553.8	TSL:1	c.2593C>T	p.Arg865Cys	missense	Exon 19 of 21	ENSP00000360608.3	Q05586-6
	GRIN1	ENST00000371560.5	TSL:1	c.2593C>T	p.Arg865Cys	missense	Exon 19 of 20	ENSP00000360615.3	Q05586-7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant (6)
2	-	-	Intellectual disability (2)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant;C4693325:Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	-0.0017	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.77		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554770667; hg19: chr9-140058297;