9-137163606-G-T

Variant names:

• chr9-137163606-G-T
• rs781053477
• NM_007327.4:c.2381G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The NM_007327.4(GRIN1):​c.2381G>T​(p.Arg794Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R794Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.33
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, 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: G2P, Ambry Genetics
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_007327.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-137163606-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 435376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 9-137163606-G-T is Pathogenic according to our data. Variant chr9-137163606-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3775570.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38070315). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	NM_007327.4	MANE Select	c.2381G>T	p.Arg794Leu	missense	Exon 17 of 20	NP_015566.1
	GRIN1	NM_001437330.1		c.2444G>T	p.Arg815Leu	missense	Exon 18 of 21	NP_001424259.1
	GRIN1	NM_001185090.2		c.2444G>T	p.Arg815Leu	missense	Exon 18 of 21	NP_001172019.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN1	ENST00000371561.8	TSL:1 MANE Select	c.2381G>T	p.Arg794Leu	missense	Exon 17 of 20	ENSP00000360616.3
	GRIN1	ENST00000371553.8	TSL:1	c.2444G>T	p.Arg815Leu	missense	Exon 18 of 21	ENSP00000360608.3
	GRIN1	ENST00000371560.5	TSL:1	c.2444G>T	p.Arg815Leu	missense	Exon 18 of 20	ENSP00000360615.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant Pathogenic:1 Uncertain:1

Jun 04, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GRIN1 c.2381G>T (p.Arg794Leu) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant was absent in 250830 control chromosomes. c.2381G>T has been observed de novo in an individual with features of Neurodevelopmental Disorder With Or Without Hyperkinetic Movements And Seizures, Autosomal Dominant (internal_testing). Additionally, another missense variant (p.Arg794Gln) in the same residue has been classified on the pathogenic spectrum in ClinVar, supporting the functional importance of this residue. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 3775570). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Jan 26, 2024

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Different missense changes at the same codon (p.Arg794Gln, p.Arg794Gly, p.Arg794Pro, p.Arg794Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000435376, VCV001481271, VCV001700093, VCV002023315 /PMID: 29365063). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.19
Sift	Benign	0.43	T
Sift4G	Benign	0.40	T
Polyphen		0.97	D
Vest4		0.50
MutPred		0.45		Loss of disorder (P = 0.0587)
MVP		0.80
MPC		3.6
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.76
gMVP		0.98
Mutation Taster		=27/73	disease causing

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: rs781053477; hg19: chr9-140058058;