GRIA3

Chr XXLR

glutamate ionotropic receptor AMPA type subunit 3

Also known as: GLUR-C, GLUR-K3, GLUR3, GLURC, GluA3, MRX94, MRXSW, iGluR3

NCBI Gene: 2892 ENSG00000125675 UniProt: P42263 OMIM: 305915

The protein functions as an AMPA-sensitive glutamate receptor subunit that forms ligand-gated ion channels mediating excitatory neurotransmission in the brain. Mutations cause X-linked syndromic intellectual developmental disorder (Wu type) through an X-linked recessive inheritance pattern. The high constraint scores (pLI 0.999, LOEUF 0.193) indicate that pathogenic variants likely cause disease through loss of function of this essential glutamate receptor subunit.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes composed of multiple subunits, arranged to form ligand-gated ion channels. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. The subunit encoded by this gene belongs to a family of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive glutamate receptors, and is subject to RNA editing (AGA->GGA; R->G). Alternative splicing at this locus results in different isoforms, which may vary in their signal transduction properties. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLRLOEUF 0.191 OMIM phenotype

Clinical Summary— GRIA3

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Gene-Disease Validity (ClinGen)

X-linked complex neurodevelopmental disorder · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

36 unique Pathogenic / Likely Pathogenic· 277 VUS of 730 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 4.97

OE 0.06 (0.02–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.23Z-score

OE missense 0.37 (0.32–0.42)

130 obs / 353.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.19)

0≤0.351.4

Missense OE?0.37 (0.32–0.42)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 2 / 32.6Missense obs/exp: 130 / 353.7Syn Z: 0.30

ClinVar Variant Classifications

730 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic21

VUS277

Likely Benign208

Benign53

Conflicting30

Pathogenic

Likely Pathogenic

277

VUS

208

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	11	1	0	15
Likely Pathogenic	7	14	0	0	21
VUS	14	232	28	3	277
Likely Benign	0	6	82	120	208
Benign	2	1	40	10	53
Conflicting	—				30
Total	26	264	151	133	604

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

91 pathogenic / likely-pathogenic (of 110) ClinVar copy-number / structural variants overlap GRIA3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →