rs1554770044

Positions:

• chr9-137162182-G-A

Variant summary

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

The ENST00000371561.8(GRIN1):​c.1643G>A​(p.Arg548Gln) variant causes a missense change involving the alteration of a conserved nucleotide. 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. R548G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRIN1 ENST00000371561.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 7.36

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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 9-137162182-G-A is Pathogenic according to our data. Variant chr9-137162182-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521298.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=4, Uncertain_significance=1}. Variant chr9-137162182-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN1	NM_007327.4	c.1643G>A	p.Arg548Gln	missense_variant	12/20	ENST00000371561.8	NP_015566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN1	ENST00000371561.8	c.1643G>A	p.Arg548Gln	missense_variant	12/20	1	NM_007327.4	ENSP00000360616

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1391986 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 687284

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 8 Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000521298, PMID:29720203). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29720203). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 16, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 548 of the GRIN1 protein (p.Arg548Gln). 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 (PMID: 29720203). ClinVar contains an entry for this variant (Variation ID: 521298). 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) performed at Invitae indicates that this missense variant is expected to disrupt 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 15, 2019	The GRIN1 c.1706G>A p.(Arg569Gln) missense variant, to our knowledge, has not been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 or version 4.0.0 of the Genome Aggregation Database. This variant was identified in a de novo state in the proband. Based on the available evidence, the c.1706G>A p.(Arg569Gln) variant is classified as likely pathogenic for autosomal dominant intellectual disability. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.1643G>A (p.Arg548Gln) in GRIN1 gene has been reported in a de novo heterozygous state in individuals affected with severe childhood epilepsy (Staněk D. et al., 2018). This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar as Pathogenic. The amino acid Arginine at position 548 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 25, 2022

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29720203) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;.;.;T;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.36	N;N;.;.;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.076	T;T;T;T;T;T;T
Sift4G	Benign	0.55	T;T;T;T;T;T;T
Polyphen		1.0	D;D;.;.;.;D;.
Vest4		0.38
MutPred		0.50		Gain of ubiquitination at K543 (P = 0.047);Gain of ubiquitination at K543 (P = 0.047);.;.;.;Gain of ubiquitination at K543 (P = 0.047);.;
MVP		0.77
MPC		3.4
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.34
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1554770044; hg19: chr9-140056634;