GRXCR1

protein-coding

glutaredoxin and cysteine rich domain containing 1, the group of Glutaredoxin domain containing|Protein phosphatase 1 regulatory subunits

Gene summary

This gene is one of 60 loci associated with autosomal-recessive nonsyndromic hearing impairment. This gene encodes a protein which contains GRX-like domains; these domains play a role in the S-glutathionylation of proteins and may be involved in actin organization in hair cells. [provided by RefSeq, Sep 2010]

Previous symbols:

DFNB25

MANE transcript

NM_001080476.3

Inheritance

ClinVar variants

P:18U:85B:29

Top phenotype

Deafness, autosomal recessive 25

gnomAD constraint

pLI —, LoF o/e 1.13

Max pathogenic AF

—

Genomic locus

chr4:42,892,713-43,030,658

External References & Databases

Ensembl (ENSG00000215203)

Transcript & Mutation Effects

hg38 • Region Span ~137.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 25STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013210

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 25STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013210

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 25MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013210

Submitter: Ambry Genetics

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The relationship between GRXCR1 and autosomal recessive nonsyndromic hearing loss was evaluated using the ClinGen Clinical Validity Framework as of 10/31/2017. Variants in GRXCR1 were first reported in humans with this disease as early as 2010 (Schraders et al.). At least 7 missense, nonsense, and frameshift variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 6 probands in 5 publications (20137778, 25802247, 26226137, 26445815, 26969326). Variants in this gene segregated with disease in 6 additional family members. This gene-disease association is supported by relevant expression and protein interaction studies, as well as multiple mouse models published by Odeh et al. 2010. In summary, GRXCR1 is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 4/24/2018.

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 25DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013210

Submitter: G2P

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 25AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 20137778

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRXCR1 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 100

Inborn genetic diseasesTotal: 41

Autosomal recessive nonsyndromic hearing loss 25Total: 29

not specifiedTotal: 23

GRXCR1-related disorderTotal: 16

Rare genetic deafnessTotal: 2

GRXCR1-related disordersTotal: 2

Hearing loss, autosomal recessiveTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001080476.3. 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			1 clinvar	25 clinvar		26
missense	1 clinvar	4 clinvar	82 clinvar	3 clinvar	1 clinvar	91
nonsense	4 clinvar	4 clinvar				8
start loss						0
frameshift	2 clinvar	1 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)	2 clinvar		1 clinvar			3
Total	9	9	85	28	1	132

Highest pathogenic variant AF is 0.000037205704

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001080476.3	RefSeq	NP_001073945.1	4	MANE Select
ENST00000399770.3	Ensembl	ENSP00000382670.2	4	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound
negative regulation of phosphatase activity
electron transport chain
cell redox homeostasis
vestibular receptor cell development

Molecular Function

molecular_function
electron transfer activity
protein disulfide oxidoreductase activity

Cellular Component

microvillus
stereocilium
kinocilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000399770
Coding exons: 4
Length: 137392
Individuals with no LoFs: 124749
Homozygous LoFs: 0
Heterozygous LoFs: 41
Defined: 124790
p: 0.000164

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.478	174	157	1.11	0.00000969	1895
Missense (PolyPhen)		81	74.502	1.0872		888
Synonymous	-0.487	65	60.2	1.08	0.00000353	570
Loss of Function	-0.433	15	13.3	1.13	0.00000102	143

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.00044	0.00043	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in actin filament architecture in developing stereocilia of sensory cells. {ECO:0000250}.;

Intolerance Scores

LoFtool: 0.695
RVIS EVS: 0.53
RVIS percentile EVS: 80.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0837

Gene Damage Prediction

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