USH1G

protein-coding

USH1 protein network component sans, the group of Sterile alpha motif domain containing|Ankyrin repeat domain containing

Gene summary

This gene encodes a protein that contains three ankyrin domains, a class I PDZ-binding motif and a sterile alpha motif. The encoded protein interacts with harmonin, which is associated with Usher syndrome type 1C. This protein plays a role in the development and maintenance of the auditory and visual systems and functions in the cohesion of hair bundles formed by inner ear sensory cells. Mutations in this gene are associated with Usher syndrome type 1G (USH1G). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

MANE transcript

NM_173477.5

Inheritance

ClinVar variants

P:66U:225B:128

Top phenotype

Usher syndrome, type 1G

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr17:74,916,083-74,923,256

External References & Databases

Ensembl (ENSG00000182040)

Transcript & Mutation Effects

hg38 • Region Span ~7.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Usher syndrome type 1GSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011748

Submitter: Ambry Genetics

Usher syndrome type 1GSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011748

Submitter: PanelApp Australia

Usher syndrome type 1GDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011748

Submitter: G2P

Usher syndrome type 1GDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011748

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Usher syndrome type 1GSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011748

Submitter: Labcorp Genetics (formerly Invitae)

Usher syndrome type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010168

Submitter: Orphanet

nonsyndromic genetic hearing lossNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

USH1G was associated with autosomal recessive nonsyndromic hearing loss in 2013 (Shearer et al.) At least seven probands with nine unique variants have been reported in seven publications (30029624, 25255398, 26969326, 26226137, 23804846, 25528277, 26561413). Probands identified were not scored due to insufficient phenotypic information to rule out Retinitis pigmentosa or probands presented with normal vision, but were below the age of onset for RP. This gene-disease association is supported by experimental expression evidence in 3 studies, however, studies were previously scored in the USH1G-autosomal recessive Usher syndrome curation thus were not scored in this curation. Expression data does support that the USH1G (sans) protein is expressed in relevant tissue. In summary, there is convincing evidence disputing the relationship between USH1G and autosomal recessive nonsyndromic hearing loss. More evidence is needed to either support or refute the role USH1G plays in this disease. This classification was approved by the ClinGen Hearing Loss gene curation expert panel on 5/27/19.

Clinical Genomic Database (CGD)

Usher syndrome, type 1GAR

Manifestation: Audiologic/Otolaryngologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 12588794

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to USH1G variants in ClinVar

15 Conditions Cataloged

not providedTotal: 360

Inborn genetic diseasesTotal: 66

Usher syndrome type 1GTotal: 59

not specifiedTotal: 40

USH1G-related disorderTotal: 14

Retinal dystrophyTotal: 6

Usher syndromeTotal: 6

Usher syndrome type 1Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_173477.5. 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			3 clinvar	113 clinvar		116
missense	3 clinvar	5 clinvar	222 clinvar	13 clinvar	2 clinvar	245
nonsense	12 clinvar	6 clinvar				18
start loss						0
frameshift	27 clinvar	11 clinvar				38
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar				2
Total	43	23	225	126	2	419

Highest pathogenic variant AF is 0.0003018044

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_173477.5	RefSeq	NP_775748.2	3	MANE Select
ENST00000614341.5	Ensembl	ENSP00000480279.1	3	MANE Select
NM_001282489.3	RefSeq	NP_001269418.1	2	Standard
ENST00000579243.1	Ensembl	ENSP00000462568.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound
inner ear morphogenesis
photoreceptor cell maintenance
sensory perception of light stimulus
equilibrioception

Molecular Function

protein binding
spectrin binding
identical protein binding
protein homodimerization activity

Cellular Component

photoreceptor inner segment
cytosol
plasma membrane
actin cytoskeleton
photoreceptor connecting cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000319642
Coding exons: 3
Length: 7176
Individuals with no LoFs: 125697
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 125724
p: 0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.633	280	311	0.899	0.0000232	2962
Missense (PolyPhen)		103	124.85	0.82501		1273
Synonymous	2.13	111	143	0.774	0.0000110	970
Loss of Function	1.33	9	14.5	0.623	8.54e-7	142

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000099	0.000097	rare
South Asian	0.000098	0.000098	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for normal development and maintenance of cochlear hair cell bundles. Anchoring/scaffolding protein that is a part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing. {ECO:0000269|PubMed:21709241}.;
Disease: DISEASE: Note=The first cases with non-syndromic sensorineural hearing loss based on mutations in USH1G. The hearing loss has an onset during early childhood, is progressive, and has a downsloping audiogram configuration. Ophthalmic and vestibular abnormalities are absent. {ECO:0000269|PubMed:25255398}.;

Intolerance Scores

LoFtool: 0.702
RVIS EVS: 0.73
RVIS percentile EVS: 86.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.295

Gene Damage Prediction

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