CLRN1

protein-coding

clarin 1, the group of Clarins

Gene summary

This gene encodes a protein that contains a cytosolic N-terminus, multiple helical transmembrane domains, and an endoplasmic reticulum membrane retention signal, TKGH, in the C-terminus. The encoded protein may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIIa. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

USH3
USH3A
RP61

MANE transcript

NM_174878.3

Inheritance

AR, AD

ClinVar variants

P:107U:123B:96

Top phenotype

Retinitis pigmentosa 61; Usher sydnrome, type 3A

gnomAD constraint

pLI —, LoF o/e 1.17

Max pathogenic AF

—

Genomic locus

chr3:150,926,163-150,972,727

External References & Databases

Ensembl (ENSG00000163646)

Transcript & Mutation Effects

hg38 • Region Span ~46.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Usher syndrome type 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016485

Submitter: Orphanet

Usher syndrome type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016485

Submitter: Natera

retinitis pigmentosa 61STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013610

Submitter: G2P

retinitis pigmentosa 61STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013610

Submitter: Labcorp Genetics (formerly Invitae)

Usher syndrome type 3DEFINITIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0016485

Submitter: ClinGen

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Usher syndrome type 3ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010170

Submitter: G2P

Usher syndrome type 3ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010170

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Retinitis pigmentosa 61; Usher sydnrome, type 3AAR

Manifestation: Audiologic/Otolaryngologic; Ophthalmologic

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

Comments: Hearing loss has been reported to be postlingual

Refs: 7711740; 8975700; 9719374; 11524702; 12080385; 12145752; 14569126; 15521980; 19753315; 21310491; 21675857

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLRN1 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 292

Usher syndrome type 3ATotal: 75

Usher syndrome type 3Total: 73

Retinitis pigmentosa 61Total: 56

CLRN1-related disorderTotal: 54

not specifiedTotal: 46

Inborn genetic diseasesTotal: 38

Retinal dystrophyTotal: 26

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_174878.3. 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			2 clinvar	93 clinvar	1 clinvar	96
missense	7 clinvar	22 clinvar	121 clinvar	2 clinvar		152
nonsense	8 clinvar	16 clinvar				24
start loss	1 clinvar	2 clinvar				3
frameshift	15 clinvar	27 clinvar				42
splice donor/acceptor (+/-2bp)	3 clinvar	6 clinvar				9
Total	34	73	123	95	1	326

Highest pathogenic variant AF is 0.00028073802

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_174878.3	RefSeq	NP_777367.1	3	MANE Select
ENST00000327047.6	Ensembl	ENSP00000322280.1	3	MANE Select
NM_001195794.1	RefSeq	NP_001182723.1	4	Standard
NM_001256819.2	RefSeq	NP_001243748.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
clrn1	Danio rerio	Structure: neuromast hair cell Quality: decreased functionality abnormal

Gene / Model

Organism

Observed Phenotype

clrn1

Danio rerio

Structure: neuromast hair cell

Quality: decreased functionality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

actin filament organization
visual perception
sensory perception of sound
positive regulation of lamellipodium assembly
photoreceptor cell maintenance

Cellular Component

microtubule
plasma membrane
microvillus
integral component of membrane
lamellipodium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000328863
Coding exons: 4
Length: 46837
Individuals with no LoFs: 125520
Homozygous LoFs: 2
Heterozygous LoFs: 226
Defined: 125748
p: 0.000907

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.593	150	131	1.15	0.00000667	1603
Missense (PolyPhen)		63	49.408	1.2751		600
Synonymous	0.243	49	51.2	0.957	0.00000304	482
Loss of Function	-0.488	11	9.39	1.17	4.98e-7	112

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.0071	0.0070	notable
European (Non-Finnish)	0.00042	0.00042	rare
South Asian	0	0.0	absent
Other	0.0015	0.0015	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May have a role in the excitatory ribbon synapse junctions between hair cells and cochlear ganglion cells and presumably also in analogous synapses within the retina. {ECO:0000269|PubMed:12080385}.;
Disease: DISEASE: Retinitis pigmentosa 61 (RP61) [MIM:614180]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:21310491}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.147

Intolerance Scores

LoFtool: 0.641
RVIS EVS: -0.6
RVIS percentile EVS: 17.75

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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