GRIP1

protein-coding

glutamate receptor interacting protein 1, the group of PDZ domain containing

Gene summary

This gene encodes a member of the glutamate receptor interacting protein family. The encoded scaffold protein binds to and mediates the trafficking and membrane organization of a number of transmembrane proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, May 2010]

MANE transcript

NM_001366722.1

Inheritance

ClinVar variants

P:56U:246B:305

Top phenotype

Fraser syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr12:66,347,431-67,069,162

External References & Databases

Ensembl (ENSG00000155974)

Transcript & Mutation Effects

hg38 • Region Span ~721.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fraser syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0054739

Submitter: ClinGen

Glutamate Receptor Interacting Protein 1 (GRIP1; MIM#604597) is a scaffolding protein that interacts with FRAS1/FREM protein complexes and required for their localization. The first report of GRIP1 in association with Fraser syndrome 3 was in Vogel, et.al 2012 (PMID:22510445), which reported in 2 independent fetuses with homozygous loss of function GRIP1 variants and phenotypes consistent with Fraser syndrome. Biallelic or homozygous loss of function (nonsense, frameshift, canonical splice, and deletion) variants in GRIP1 have since been reported in multiple additional affected individuals in the literature with Fraser Syndrome 3 (PMIDs:24357607, 33709629). The mechanism for GRIP1 in association with Fraser Syndrome 3 is loss of function and it is inherited in an autosomal recessive pattern. GRIP1 knockout mouse models have variable background dependent phenotypes including embryonic lethality with severe bullous disorder, haemorrhagic bullae, limb malformations including syndactyly and polydactyly, uni- or bilateral cryptophthalmos, and absent kidneys (PMIDs:11983858, 14730302). GRIP1 localization studies in mouse and in vitro models demonstrate the presence of GRIP1 at the basal cell layer in developing epidermis and co-localization with Fras1 and Frem2 in epithelial cells (PMID:11983858, 14730302). Given the genetic and functional evidence, GRIP1 is classified as Definitive for Fraser Syndrome 3. Of note, missense variants in GRIP1 have also been implicated in Congential Anomalies of the Kidney and Urinary Tract (CAKUT) (PMID:24700879, 26489027, 26539891, 33226606), however curation of GRIP1 for CAKUT and associated phenotypes is out of the scope of the Prenatal Gene Curation Expert Panel.

Fraser syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054739

Submitter: PanelApp Australia

Fraser syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054739

Submitter: Labcorp Genetics (formerly Invitae)

Fraser syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054739

Submitter: G2P

Fraser syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009046

Submitter: Orphanet

Fraser syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0054739

Submitter: Natera

Clinical Genomic Database (CGD)

Fraser syndrome 3AR

Manifestation: Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 22510445; 30280376

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRIP1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 574

Fraser syndrome 3Total: 196

Inborn genetic diseasesTotal: 134

not specifiedTotal: 38

GRIP1-related disorderTotal: 37

Intellectual disabilityTotal: 3

Fraser syndrome 1Total: 2

Abnormal brain morphologyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001366722.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	288 clinvar		292
missense		1 clinvar	236 clinvar	14 clinvar	3 clinvar	254
nonsense	14 clinvar	5 clinvar	3 clinvar			22
start loss			1 clinvar			1
frameshift	21 clinvar	4 clinvar				25
splice donor/acceptor (+/-2bp)	1 clinvar	10 clinvar	2 clinvar			13
Total	36	20	246	302	3	607

Highest pathogenic variant AF is 0.0000272739

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001366722.1	RefSeq	NP_001353651.1	25	MANE Select
ENST00000359742.9	Ensembl	ENSP00000352780.4	25	MANE Select
NM_001178074.2	RefSeq	NP_001171545.1	23	Standard
NM_001366723.1	RefSeq	NP_001353652.1	24	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
grip1	Danio rerio	Structure: whole organism Quality: viability abnormal

Gene / Model

Organism

Observed Phenotype

grip1

Danio rerio

Structure: whole organism

Quality: viability

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Brain-Derived Neurotrophic Factor (BDNF) signaling pathway
carm1 and regulation of the estrogen receptor
role of erbb2 in signal transduction and oncology
Neuronal System
Trafficking of GluR2-containing AMPA receptors

Biological Process

dendrite development
androgen receptor signaling pathway
intracellular signal transduction
positive regulation of transcription, DNA-templated
neurotransmitter receptor transport, endosome to postsynaptic membrane

Molecular Function

transcription coactivator activity
protein binding
beta-catenin binding
protein C-terminus binding
receptor signaling complex scaffold activity

Cellular Component

endoplasmic reticulum
cytosol
plasma membrane
cell junction
cytoplasmic vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000398016
Coding exons: 24
Length: 456756
Individuals with no LoFs: 124755
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 124797
p: 0.000168

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.58	478	586	0.816	0.0000334	7006
Missense (PolyPhen)		104	179.21	0.58032		2096
Synonymous	-0.500	238	228	1.04	0.0000138	2181
Loss of Function	5.34	12	54.6	0.220	0.00000314	641

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.00046	0.00046	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.000098	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role as a localized scaffold for the assembly of a multiprotein signaling complex and as mediator of the trafficking of its binding partners at specific subcellular location in neurons (PubMed:10197531). Through complex formation with NSG1, GRIA2 and STX12 controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting (By similarity). {ECO:0000250|UniProtKB:P97879, ECO:0000269|PubMed:10197531}.;
Disease: DISEASE: Fraser syndrome 3 (FRASRS3) [MIM:617667]: A form of Fraser syndrome, an autosomal recessive disorder characterized by cryptophthalmos, cutaneous syndactyly, and urogenital abnormalities including renal agenesis or hypoplasia. Additional features include abnormalities of the larynx, ear malformations, and facial abnormalities. {ECO:0000269|PubMed:22510445}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.276

Intolerance Scores

LoFtool: 0.566
RVIS EVS: -0.53
RVIS percentile EVS: 20.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.613

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium