rs1554770243

Positions:

• chr9-137162653-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The ENST00000371561.8(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 Conflicting classifications of pathogenicity (no stars). 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 ENST00000371561.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.71

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000371561.8
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GRIN1. . Gene score misZ 6.2157 (greater than the threshold 3.09). Trascript score misZ 6.6419 (greater than threshold 3.09). GenCC has associacion of gene with 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 9-137162653-A-G is Pathogenic according to our data. Variant chr9-137162653-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539837.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.1927A>G	p.Ile643Val	missense_variant	14/20	ENST00000371561.8	NP_015566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8	c.1927A>G	p.Ile643Val	missense_variant	14/20	1	NM_007327.4	ENSP00000360616

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Dec 02, 2022

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). -

Intellectual disability, autosomal dominant 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2023

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 variant has not been reported in the literature in individuals affected with GRIN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 539837). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
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

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: rs1554770243; hg19: chr9-140057105;