GRXCR2

protein-coding

glutaredoxin and cysteine rich domain containing 2, the group of Glutaredoxin domain containing

Gene summary

This gene encodes a protein containing a glutaredoxin domain, which functions in protein S-glutathionylation. A mutation in this gene was found in a family with autoosomal recessive nonsyndromic sensorineural deafness-101. [provided by RefSeq, Jun 2014]

MANE transcript

NM_001080516.2

Inheritance

ClinVar variants

P:7U:57B:28

Top phenotype

Deafness, autosomal recessive 101

gnomAD constraint

pLI —, LoF o/e 0.96

Max pathogenic AF

—

Genomic locus

chr5:145,858,521-145,937,126

External References & Databases

Ensembl (ENSG00000204928)

Transcript & Mutation Effects

hg38 • Region Span ~78.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 101STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014363

Submitter: Labcorp Genetics (formerly Invitae)

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

GRXCR2 was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2014 by Imtiaz et al. One missense variant occurring in the last exon and resulting in an extension has been reported to segregate with disease in a family with hearing loss. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. This gene-disease association is supported by multiple mouse models, functional alteration studies, protein interaction studies indicating that GRXCR2 interacts with TPRN, and inner ear expression studies (Avenarious et al. 2012, 30157177; Avenarius 2012, a PhD thesis; Liu et al. 2018, 30380417). In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Working Group on 3/26/2021.

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 101STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014363

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 101AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 24619944

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRXCR2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 64

not specifiedTotal: 48

GRXCR2-related disorderTotal: 8

Autosomal recessive nonsyndromic hearing loss 101Total: 6

Hearing loss, autosomal recessiveTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001080516.2. 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	22 clinvar	1 clinvar	24
missense	1 clinvar		54 clinvar	5 clinvar		60
nonsense	2 clinvar	3 clinvar	1 clinvar			6
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	4	3	57	27	1	92

Highest pathogenic variant AF is 0.00003808858

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_001080516.2	RefSeq	NP_001073985.1	3	MANE Select
ENST00000377976.3	Ensembl	ENSP00000367214.1	3	MANE Select
ENST00000639411.1	Ensembl	ENSP00000491860.1	2	Standard
ENST00000639411.2	Ensembl	ENSP00000491860.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound

Cellular Component

microvillus
stereocilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377976
Coding exons: 3
Length: 13236
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 38
Defined: 125746
p: 0.000151

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.853	167	139	1.20	0.00000751	1641
Missense (PolyPhen)		64	57.379	1.1154		663
Synonymous	-0.866	63	54.8	1.15	0.00000304	458
Loss of Function	0.134	11	11.5	0.957	8.00e-7	123

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.00017	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.00023	0.00023	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Could play a role in maintaining cochlear stereocilia bundles that are involved in sound detection. {ECO:0000269|PubMed:24619944}.;
Disease: DISEASE: Deafness, autosomal recessive, 101 (DFNB101) [MIM:615837]: A form of non-syndromic deafness characterized by bilateral, moderate to severe hearing loss. Vestibular function is unaffected. {ECO:0000269|PubMed:24619944}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.600
RVIS EVS: 0.71
RVIS percentile EVS: 85.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.106

Gene Damage Prediction

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