9-137162510-G-C

Position:

• chr9-137162510-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_007327.4(GRIN1):​c.1858G>C​(p.Gly620Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• 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: 7.34

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_007327.4 (GRIN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 9-137162510-G-C is Pathogenic according to our data. Variant chr9-137162510-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.1858G>C	p.Gly620Arg	missense_variant	13/20	ENST00000371561.8	NP_015566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8	c.1858G>C	p.Gly620Arg	missense_variant	13/20	1	NM_007327.4	ENSP00000360616.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 21, 2014	Likely pathogenicity based on finding it twice in our laboratory de novo: in a 24-year-old female with absent speech, autism, intellectual disability, mild unilateral conductive hearing loss, spasticity, joint laxity, failure to thrive, gastroesophageal disorder, strabismus, myopia, mild mitral valve prolapse, intermittent episodes of syncope, and scoliosis; in a 7-year-old male with absent speech, regression, intellectual disability, congenital hypotonia, movement disorder, short stature -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 620 of the GRIN1 protein (p.Gly620Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant GRIN1-related conditions (PMID: 28228639, 34884460). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 209159). 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. Experimental studies have shown that this missense change affects GRIN1 function (PMID: 28228639, 31429998). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2022	Variant summary: GRIN1 c.1858G>C (p.Gly620Arg) results in a non-conservative amino acid change located in the Ionotropic glutamate receptor domain (IPR001320) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 244402 control chromosomes. c.1858G>C has been reported in the literature as a de-novo variant in multiple individuals affected with features of Autosomal Dominant Neurodevelopmental Disorder With Or Without Hyperkinetic Movements And Seizures (example, Chen_2017, Lemke_2016, Costain_2019, Li_2019, Santos-Gomez_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting a reduction in N-methyl-D-aspartate (NMDAR) receptor trafficking, expression and function (example, Chen_2017). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	GRIN1: PS2, PM1, PM2, PP2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2023	Published functional studies demonstrate a damaging effect: loss of NMDA receptor function (Lemke et al., 2016; Chen et al., 2017); 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: 27164704, 26633545, 28228639, 31487502, 31429998) -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 19, 2021	PS3, PP2, PP3, PM1, PM2, PS4_Moderate -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2018

The p.G620R variant (also known as c.1858G>C), located in coding exon 13 of the GRIN1 gene, results from a G to C substitution at nucleotide position 1858. The glycine at codon 620 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in individuals with intellectual disability and has been shown to have an impact on protein function (Lemke JR et al. Neurology, 2016 06;86:2171-8; Chen W et al. J. Hum. Genet., 2017 Jun;62:589-597). In addition, this variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with global developmental delay and hypotonia (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Seizure Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;D;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.0	M;M;.;.;.;M;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.1	D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0050	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		0.83
MutPred		0.82		Gain of MoRF binding (P = 0.0372);Gain of MoRF binding (P = 0.0372);.;.;.;Gain of MoRF binding (P = 0.0372);.;
MVP		0.91
MPC		2.8
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.80
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: rs797045047; hg19: chr9-140056962;