chr9-137162653-A-G

Variant names:

• chr9-137162653-A-G
• rs1554770243
• NM_007327.4:c.1927A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_007327.4(GRIN1):​c.1927A>G​(p.Ile643Val) 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. I643T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRIN1 NM_007327.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.71
• 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: 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 24 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_007327.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-137162653-A-G is Pathogenic according to our data. Variant chr9-137162653-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 539837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.1927A>G	p.Ile643Val	missense_variant	Exon 14 of 20	ENST00000371561.8	NP_015566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8	c.1927A>G	p.Ile643Val	missense_variant	Exon 14 of 20	1	NM_007327.4	ENSP00000360616.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 1 Pathogenic:1

Dec 02, 2022

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The novel genetic variant identified in case (NM_007327.4:c.1927A>G-p.Ile643Val) affects a highly conserved amino acid in the second segment (S2) of the extracellular LBD involved in binding the co-agonists glutamate and glycine/D-serine. Specifically, the Ile643 position is located in the loop that connects the LBD with the TMD, a loop that is also involved in the interaction between subunits of the NMDA. In turn, in a previous study in which pathogenic and non-pathogenic variants were mapped to the structure of NMDA, it was shown that this loop is extremely critical and that all the variants reported in this region affect protein function. Therefore, the structural prediction would be pathogenic; however, since we do not have functional studies that demonstrate the gain or loss of function, the variant was classified as likely pathogenic according to the ACMG guidelines (PM1, PM2, PP2, PP3). -

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

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 643 of the GRIN1 protein (p.Ile643Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GRIN1-related conditions (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 539837). 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%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;.;T;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.3	L;L;.;.;.;L;.
PhyloP100		5.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.61	N;N;N;N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.055	T;T;D;D;D;T;T
Sift4G	Uncertain	0.058	T;T;T;T;T;T;T
Polyphen		0.88	P;P;.;.;.;P;.
Vest4		0.55
MutPred		0.77		Gain of catalytic residue at I643 (P = 0.0077);Gain of catalytic residue at I643 (P = 0.0077);.;.;.;Gain of catalytic residue at I643 (P = 0.0077);.;
MVP		0.84
MPC		2.8
ClinPred		0.88	D
GERP RS		4.5
Varity_R		0.43
gMVP		0.93
Mutation Taster		=43/57	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: rs1554770243; hg19: chr9-140057105;