autosomal recessive nonsyndromic hearing loss 1B

Summary

autosomal recessive nonsyndromic hearing loss 1B (MONDO:0012977) is a disease caused by GJB6 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: GJB6 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 116

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive nonsyndromic hearing loss 1B
Mondo ID	MONDO:0012977
MeSH	C567213
OMIM	612645
DOID	DOID:0110476
UMLS	C2675235
MedGen	436381
GARD	0022629
Is cancer (heuristic)	no

Also known as: autosomal recessive deafness 1B · Autosomal recessive deafness type 1B · autosomal recessive nonsyndromic deafness 1B · autosomal recessive nonsyndromic deafness caused by mutation in GJB6 · autosomal recessive nonsyndromic deafness type 1B · deafness, autosomal recessive 1B · deafness, autosomal recessive 1b · deafness, autosomal recessive type 1B · DFNB1B · GJB6 autosomal recessive nonsyndromic deafness

Data availability: 116 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › hearing loss, autosomal recessive › autosomal recessive nonsyndromic hearing loss 1B

Related subtypes (101): autosomal recessive nonsyndromic hearing loss 5, autosomal recessive nonsyndromic hearing loss 1A, autosomal recessive nonsyndromic hearing loss 2, autosomal recessive nonsyndromic hearing loss 3, autosomal recessive nonsyndromic hearing loss 4, autosomal recessive nonsyndromic hearing loss 6, autosomal recessive nonsyndromic hearing loss 7, autosomal recessive nonsyndromic hearing loss 9, autosomal recessive nonsyndromic hearing loss 8, autosomal recessive nonsyndromic hearing loss 12, autosomal recessive nonsyndromic hearing loss 15, autosomal recessive nonsyndromic hearing loss 18A, autosomal recessive nonsyndromic hearing loss 17, autosomal recessive nonsyndromic hearing loss 13, autosomal recessive nonsyndromic hearing loss 21, autosomal recessive nonsyndromic hearing loss 14, autosomal recessive nonsyndromic hearing loss 16, autosomal recessive nonsyndromic hearing loss 20, autosomal recessive nonsyndromic hearing loss 26, autosomal recessive nonsyndromic hearing loss 27, autosomal recessive nonsyndromic hearing loss 22, autosomal recessive nonsyndromic hearing loss 31, autosomal recessive nonsyndromic hearing loss 30, autosomal recessive nonsyndromic hearing loss 33, autosomal recessive nonsyndromic hearing loss 37, autosomal recessive nonsyndromic hearing loss 38, autosomal recessive nonsyndromic hearing loss 40, autosomal recessive nonsyndromic hearing loss 39, autosomal recessive nonsyndromic hearing loss 35, autosomal recessive nonsyndromic hearing loss 32, autosomal recessive nonsyndromic hearing loss 36, autosomal recessive nonsyndromic hearing loss 48, autosomal recessive nonsyndromic hearing loss 23, autosomal recessive nonsyndromic hearing loss 42, autosomal recessive nonsyndromic hearing loss 46, autosomal recessive nonsyndromic hearing loss 53, autosomal recessive nonsyndromic hearing loss 28, autosomal recessive nonsyndromic hearing loss 51, autosomal recessive nonsyndromic hearing loss 47, autosomal recessive nonsyndromic hearing loss 55, autosomal recessive nonsyndromic hearing loss 62, autosomal recessive nonsyndromic hearing loss 49, autosomal recessive nonsyndromic hearing loss 44, autosomal recessive nonsyndromic hearing loss 66, autosomal recessive nonsyndromic hearing loss 59, autosomal recessive nonsyndromic hearing loss 65, autosomal recessive nonsyndromic hearing loss 67, autosomal recessive nonsyndromic hearing loss 68, autosomal recessive nonsyndromic hearing loss 24, autosomal recessive nonsyndromic hearing loss 63, autosomal recessive nonsyndromic hearing loss 45, autosomal recessive nonsyndromic hearing loss 71, autosomal recessive nonsyndromic hearing loss 77, autosomal recessive nonsyndromic hearing loss 25, autosomal recessive nonsyndromic hearing loss 79, autosomal recessive nonsyndromic hearing loss 84A, autosomal recessive nonsyndromic hearing loss 85, autosomal recessive nonsyndromic hearing loss 91, autosomal recessive nonsyndromic hearing loss 83, autosomal recessive nonsyndromic hearing loss 74, autosomal recessive nonsyndromic hearing loss 61, autosomal recessive nonsyndromic hearing loss 89, autosomal recessive nonsyndromic hearing loss 29, autosomal recessive nonsyndromic hearing loss 96, autosomal recessive nonsyndromic hearing loss 86, autosomal recessive nonsyndromic hearing loss 98, autosomal recessive nonsyndromic hearing loss 93, autosomal recessive nonsyndromic hearing loss 70, autosomal recessive nonsyndromic hearing loss 84B, autosomal recessive nonsyndromic hearing loss 18B, autosomal recessive nonsyndromic hearing loss 88, autosomal recessive nonsyndromic hearing loss 76, autosomal recessive nonsyndromic hearing loss 101, autosomal recessive nonsyndromic hearing loss 102, autosomal recessive nonsyndromic hearing loss 103, autosomal recessive nonsyndromic hearing loss 104, autosomal recessive nonsyndromic hearing loss 97, hearing loss, autosomal recessive 111, hearing loss, autosomal recessive 118, with cochlear aplasia, hearing loss, autosomal recessive 119, hearing loss, autosomal recessive 117, hearing loss, autosomal recessive 112, hearing loss, autosomal recessive 113, hearing loss, autosomal recessive 100, hearing loss, autosomal recessive 94, hearing loss, autosomal recessive 114, hearing loss, autosomal recessive 115, hearing loss, autosomal recessive 99, hearing loss, autosomal recessive 106, hearing loss, autosomal recessive 107, hearing loss, autosomal recessive 108, hearing loss, autosomal recessive 57, hearing loss, autosomal recessive 109, hearing loss, autosomal recessive 116, hearing loss, autosomal recessive 110, hearing loss, autosomal recessive 120, hearing loss, autosomal recessive 121, hearing loss, autosomal recessive 122, hearing loss, autosomal recessive 123, autosomal recessive nonsyndromic hearing loss 124, hearing loss, autosomal recessive 125

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

116 retrieved; paginated sample, class counts are floors:

53 uncertain significance, 19 likely benign, 16 pathogenic, 14 conflicting classifications of pathogenicity, 8 benign/likely benign, 5 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2500795	NC_000013.11:g.20222821_20531941del	CRYL1	Pathogenic	criteria provided, single submitter
915994	GRCh37/hg19 13q12.11(chr13:20803674-21030220)	CRYL1	Pathogenic	no assertion criteria provided
17000	NM_004004.6(GJB2):c.101T>C (p.Met34Thr)	GJB2	Pathogenic	reviewed by expert panel
17001	NM_004004.6(GJB2):c.231G>A (p.Trp77Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17002	NM_004004.6(GJB2):c.71G>A (p.Trp24Ter)	GJB2	Pathogenic	reviewed by expert panel
17003	NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17004	NM_004004.6(GJB2):c.35del (p.Gly12fs)	GJB2	Pathogenic	reviewed by expert panel
17010	NM_004004.6(GJB2):c.167del (p.Leu56fs)	GJB2	Pathogenic	reviewed by expert panel
17014	NM_004004.6(GJB2):c.235del (p.Leu79fs)	GJB2	Pathogenic	reviewed by expert panel
17016	NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17023	NM_004004.6(GJB2):c.109G>A (p.Val37Ile)	GJB2	Pathogenic	reviewed by expert panel
17029	NM_004004.6(GJB2):c.-23+1G>A	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
44736	NM_004004.6(GJB2):c.299_300del (p.His100fs)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
44737	NM_004004.6(GJB2):c.313_326del (p.Lys105fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
44749	NM_004004.6(GJB2):c.416G>A (p.Ser139Asn)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
44763	NM_004004.6(GJB2):c.617A>G (p.Asn206Ser)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072828	NC_000013.10:g.(?_20797176)_21105944del	GJB6	Pathogenic	criteria provided, single submitter
4783767	NM_001110219.3(GJB6):c.31G>C (p.Gly11Arg)	GJB6	Pathogenic	criteria provided, single submitter
5544	NM_001110219.3(GJB6):c.31G>A (p.Gly11Arg)	GJB6	Pathogenic	criteria provided, multiple submitters, no conflicts
5545	NM_001110219.3(GJB6):c.263C>T (p.Ala88Val)	GJB6	Pathogenic	criteria provided, multiple submitters, no conflicts
5546	del(GJB6-D13S1830)	LOC130009323	Pathogenic	no assertion criteria provided
44740	NM_004004.6(GJB2):c.34G>T (p.Gly12Cys)	GJB2	Likely pathogenic	reviewed by expert panel
1474469	NM_001110219.3(GJB6):c.223C>T (p.Arg75Trp)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196442	NM_001110219.3(GJB6):c.177A>G (p.Gly59=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1967071	NM_001110219.3(GJB6):c.94C>T (p.Arg32Ter)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225377	NM_001110219.3(GJB6):c.301G>A (p.Glu101Lys)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285401	NM_001110219.3(GJB6):c.672A>G (p.Arg224=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
311381	NM_001110219.3(GJB6):c.405G>A (p.Thr135=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
311382	NM_001110219.3(GJB6):c.63del (p.Lys22fs)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
311383	NM_001110219.3(GJB6):c.60C>T (p.Ile20=)	GJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GJB6	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 3B	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJB6	Orphanet:189	Hidrotic ectodermal dysplasia
GJB6	Orphanet:477	KID syndrome
GJB6	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB6	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJB2	Orphanet:166286	Porokeratotic eccrine ostial and dermal duct nevus
GJB2	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
GJB2	Orphanet:2698	Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome
GJB2	Orphanet:477	KID syndrome
GJB2	Orphanet:494	Keratoderma hereditarium mutilans
GJB2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GJB6	HGNC:4288	ENSG00000121742	O95452	Gap junction beta-6 protein	gencc,clinvar
CRYL1	HGNC:18246	ENSG00000165475	Q9Y2S2	Lambda-crystallin homolog	clinvar
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJB6	Gap junction beta-6 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
CRYL1	Lambda-crystallin homolog	Catalyzes the conversion of L-gulonate to 3-dehydro-L-gulonate.
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GJB6	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS
CRYL1	Other/Unknown	no		3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd, 3-OHacyl-CoA_DH_CS
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	2
gingival epithelium	2
upper arm skin	1
C1 segment of cervical spinal cord	1
adult mammalian kidney	1
right lobe of liver	1
penis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJB6	187	broad	marker	upper arm skin, gingiva, gingival epithelium
CRYL1	268	ubiquitous	marker	adult mammalian kidney, right lobe of liver, C1 segment of cervical spinal cord
GJB2	196	broad	marker	gingival epithelium, gingiva, penis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRYL1	2,064
GJB2	1,391
GJB6	1,219

Intra-cohort edges

A	B	Sources
GJB2	GJB6	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB2	P29033	24
CRYL1	Q9Y2S2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJB6	O95452	82.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Gap junction assembly	2	195.2×	2e-04	GJB6, GJB2
Oligomerization of connexins into connexons	1	1268.9×	0.001	GJB2
Transport of connexins along the secretory pathway	1	1268.9×	0.001	GJB2
Formation of xylulose-5-phosphate	1	634.4×	0.002	CRYL1
Transport of connexons to the plasma membrane	1	181.3×	0.006	GJB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gap junction-mediated intercellular transport	2	1872.4×	4e-06	GJB6, GJB2
gap junction assembly	2	1404.3×	4e-06	GJB6, GJB2
transmembrane transport	2	112.3×	5e-04	GJB6, GJB2
sensory perception of sound	2	67.3×	0.001	GJB6, GJB2
ear morphogenesis	1	1404.3×	0.002	GJB6
cell-cell signaling	2	46.4×	0.002	GJB6, GJB2
obsolete D-glucuronate catabolic process to D-xylulose 5-phosphate	1	936.2×	0.002	CRYL1
sinoatrial node development	1	702.2×	0.003	GJB6
response to electrical stimulus	1	216.1×	0.008	GJB6
maintenance of blood-brain barrier	1	160.5×	0.009	GJB6
inner ear development	1	124.8×	0.011	GJB6
cellular response to glucose stimulus	1	89.2×	0.014	GJB6
fatty acid metabolic process	1	64.6×	0.018	CRYL1
response to lipopolysaccharide	1	41.6×	0.026	GJB6
negative regulation of cell population proliferation	1	14.0×	0.070	GJB6

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GJB2	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJB2	1	4
GJB6	0	0
CRYL1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GJB2	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
KANAMYCIN	4	GJB2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJB2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	GJB6, CRYL1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GJB6	0	GJB2
CRYL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.