ADGRV1

protein-coding

adhesion G protein-coupled receptor V1, the group of USH2 complex |Adhesion G protein-coupled receptors, subfamily V

Gene summary

This gene encodes a member of the G-protein coupled receptor superfamily. The encoded protein contains a 7-transmembrane receptor domain, binds calcium and is expressed in the central nervous system. Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. Several alternatively spliced transcripts have been described. [provided by RefSeq, Jul 2008]

Previous symbols:

USH2C
MASS1
GPR98

MANE transcript

NM_032119.4

Inheritance

AD, AR, Digenic

ClinVar variants

P:727U:2238B:2941

Top phenotype

Usher syndrome, type IIC

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr5:90,529,344-91,164,437

External References & Databases

Ensembl (ENSG00000164199)

Transcript & Mutation Effects

hg38 • Region Span ~635.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

febrile seizures, familial, 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011443

Submitter: Ambry Genetics

Usher syndrome type 2CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011558

Submitter: PanelApp Australia

Usher syndrome type 2CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011558

Submitter: Labcorp Genetics (formerly Invitae)

febrile seizures, familial, 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011443

Submitter: PanelApp Australia

Usher syndrome type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016484

Submitter: ClinGen

nonsyndromic genetic hearing lossNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

ADGRV1, previously known as GPR98, was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2013 (Yang et al., 23767834). At least 27 unique variants (missense, nonsense, frameshift, splice-site) have been reported in humans. Variants in this gene have been reported in at least 17 probands in 11 publications (23804846, 24123792, 23767834, 25528277, 25719458, 24853665, 29048421, 26226137, 26445815, 27068579, 28951997). Evidence disputing this gene-disease relationship includes lack of age information, lack of clinical examination history, and high allele frequency of variants in population databases. Of note, this gene has also been implicated in Usher syndrome Type 2. This has been assessed separately as Definitive. The mechanism of disease of ADGRV1-Usher syndrome Type 2 is homozygous loss of function, which is consistent with the variants reported in ADGRV1-nonsyndomic hearing loss patients. In summary, there is convincing evidence disputing the relationship between ADGRV1 and autosomal recessive nonsyndromic hearing loss. More evidence is needed to either support or refute the role ADGRV1 plays in this disease. This classification was approved by the ClinGen Hearing Loss Working Group on 3/19/19 (SOP Version 6).

Usher syndrome type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016484

Submitter: Orphanet

Usher syndrome type 2CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011558

Submitter: G2P

Clinical Genomic Database (CGD)

Usher syndrome, type IICAR/Digenic

Manifestation: Audiologic/Otolaryngologic; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: Digenic inheritance has been described (with PDZD7)

Refs: 12402266; 14740321; 16273391;19357116; 18854872; 0440071; 21174530

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADGRV1 variants in ClinVar

36 Conditions Cataloged

not providedTotal: 6398

not specifiedTotal: 1080

Inborn genetic diseasesTotal: 832

ADGRV1-related disorderTotal: 761

Usher syndrome type 2CTotal: 611

Febrile seizures, familial, 4Total: 217

Usher syndromeTotal: 46

Retinal dystrophyTotal: 45

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032119.4. 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	1 clinvar		28 clinvar	1836 clinvar	19 clinvar	1884
missense	3 clinvar	31 clinvar	2196 clinvar	1038 clinvar	48 clinvar	3316
nonsense	142 clinvar	73 clinvar	2 clinvar			217
start loss		1 clinvar	1 clinvar			2
frameshift	234 clinvar	121 clinvar	6 clinvar			361
splice donor/acceptor (+/-2bp)	21 clinvar	100 clinvar	5 clinvar			126
Total	401	326	2238	2874	67	5906

Highest pathogenic variant AF is 0.000077022174

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032119.4	RefSeq	NP_115495.3	90	MANE Select
ENST00000405460.9	Ensembl	ENSP00000384582.2	90	MANE Select
ENST00000425867.3	Ensembl	ENSP00000392618.3	38	Standard
ENST00000450321.2	Ensembl	ENSP00000492054.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

GPCRs, Other

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000405460
Coding exons: 90
Length: 634878
Individuals with no LoFs: 124366
Homozygous LoFs: 0
Heterozygous LoFs: 313
Defined: 124679
p: 0.00126

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0740	3130	3.14e+3	0.996	0.000160	41060
Missense (PolyPhen)		852	944.78	0.9018		12042
Synonymous	-0.554	1179	1.16e+3	1.02	0.0000632	12548
Loss of Function	8.19	110	250	0.441	0.0000132	3267

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0013	0.0013	notable
Latino/Admixed American	0.00099	0.00099	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0014	0.0013	notable
Finnish	0.00061	0.00060	rare
European (Non-Finnish)	0.0014	0.0014	notable
South Asian	0.0019	0.0018	notable
Other	0.0017	0.0017	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor that may have an important role in the development of the central nervous system.;
Disease: DISEASE: Usher syndrome 2C (USH2C) [MIM:605472]: USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH2 is characterized by congenital mild hearing impairment with normal vestibular responses. {ECO:0000269|PubMed:14740321, ECO:0000269|PubMed:22147658}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Febrile seizures, familial, 4 (FEB4) [MIM:604352]: Seizures associated with febrile episodes in childhood without any evidence of intracranial infection or defined pathologic or traumatic cause. It is a common condition, affecting 2-5% of children aged 3 months to 5 years. The majority are simple febrile seizures (generally defined as generalized onset, single seizures with a duration of less than 30 minutes). Complex febrile seizures are characterized by focal onset, duration greater than 30 minutes, and/or more than one seizure in a 24 hour period. The likelihood of developing epilepsy following simple febrile seizures is low. Complex febrile seizures are associated with a moderately increased incidence of epilepsy. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.170

Intolerance Scores

RVIS EVS: 8.12
RVIS percentile EVS: 99.95

Essentials

Essential (gene trap): N