KLHL7

Summary

KLHL7 (kelch like family member 7, HGNC:15646) is a protein-coding gene on chromosome 7p15.3, encoding Kelch-like protein 7 (Q8IXQ5). Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex.

This gene encodes a BTB-Kelch-related protein. The encoded protein may be involved in protein degradation. Mutations in this gene have been associated with retinitis pigmentosa 42.

Source: NCBI Gene 55975 — RefSeq curated summary.

At a glance

• Gene–disease (curated): PERCHING syndrome (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 530 total — 23 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 52
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• MANE Select transcript: NM_001031710

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15646
Approved symbol	KLHL7
Name	kelch like family member 7
Location	7p15.3
Locus type	gene with protein product
Status	Approved
Aliases	KLHL6, SBBI26, RP42
Ensembl gene	ENSG00000122550
Ensembl biotype	protein_coding
OMIM	611119
Entrez	55975

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 11 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000322275, ENST00000339077, ENST00000409689, ENST00000410047, ENST00000414163, ENST00000459661, ENST00000469576, ENST00000469845, ENST00000477076, ENST00000479288, ENST00000479700, ENST00000491352, ENST00000521082, ENST00000895457, ENST00000895458, ENST00000923179, ENST00000923180, ENST00000952765, ENST00000952766

RefSeq mRNA: 3 — MANE Select: NM_001031710 NM_001031710, NM_001172428, NM_018846

CCDS: CCDS34609, CCDS5378, CCDS55095

Canonical transcript exons

ENST00000339077 — 11 exons

Exon	Start	End
ENSE00000976499	23174015	23177914
ENSE00001873314	23105785	23106146
ENSE00003479914	23125048	23125172
ENSE00003550309	23152067	23152209
ENSE00003556714	23124688	23124781
ENSE00003582882	23140769	23140944
ENSE00003606599	23172948	23173045
ENSE00003634833	23143851	23144025
ENSE00003650994	23123777	23123879
ENSE00003659705	23165698	23165938
ENSE00003688228	23167836	23168037

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 99.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.4904 / max 182.1816, expressed in 1813 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77613	18.2197	1811
77614	0.6007	239
77612	0.3197	143
77617	0.2240	101
77616	0.0792	34
77615	0.0264	10
77618	0.0129	2
77619	0.0078	2

Top tissues by expression

286 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.39	gold quality
secondary oocyte	CL:0000655	99.17	gold quality
heart right ventricle	UBERON:0002080	98.55	gold quality
sperm	CL:0000019	97.85	gold quality
ganglionic eminence	UBERON:0004023	97.58	gold quality
cortical plate	UBERON:0005343	97.22	gold quality
left testis	UBERON:0004533	96.46	gold quality
right testis	UBERON:0004534	96.26	gold quality
male germ cell	CL:0000015	96.23	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.64	gold quality
ventricular zone	UBERON:0003053	95.47	gold quality
cardiac ventricle	UBERON:0002082	95.00	gold quality
left ventricle myocardium	UBERON:0006566	94.94	gold quality
heart left ventricle	UBERON:0002084	94.91	gold quality
testis	UBERON:0000473	94.82	gold quality
myocardium	UBERON:0002349	94.55	gold quality
heart	UBERON:0000948	93.84	gold quality
germinal epithelium of ovary	UBERON:0001304	93.61	gold quality
cardiac atrium	UBERON:0002081	93.61	gold quality
right atrium auricular region	UBERON:0006631	93.58	gold quality
substantia nigra pars compacta	UBERON:0001965	93.37	gold quality
pons	UBERON:0000988	93.31	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.26	gold quality
pigmented layer of retina	UBERON:0001782	93.19	gold quality
apex of heart	UBERON:0002098	93.04	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.88	gold quality
middle temporal gyrus	UBERON:0002771	92.65	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.42	gold quality
adrenal tissue	UBERON:0018303	92.21	gold quality
vena cava	UBERON:0004087	92.15	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.82
E-MTAB-6379	no	1403.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

101 targeting KLHL7, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192

Literature-anchored findings (GeneRIF, showing 13)

• The present results indicate that KLHL7 antibodies are associated with various cancers, and in some patients also with neurological disease. Whether KLHL7 antibodies can be used as paraneoplastic markers for PNS remains to be determined. (PMID:16918702)
• Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa. (PMID:19520207)
• Observed in 2 Scandinavian families to date, KLHL7 mutation has recently been associated with autosomal dominant retinitis pigmentosa. (PMID:20547956)
• KLHL7 forms a dimer, assembles with Cul3 through its BTB and BACK domains, and exerts E3 activity. (PMID:21828050)
• The phenotypes are similar among patients with 3 types of KLHL7 mutations (c.458C>T, c.449G>A, and c.457G>A). (PMID:22084217)
• data further support the pathogenic role of KLHL7 mutations in a CS/CISS1-like phenotype–but they do not explain all their clinical manifestations and highlight the high phenotypic heterogeneity associated with mutations in KLHL7 (PMID:27392078)
• KLHL7 is a novel regulator of the nucleolus associated with TUT1 ubiquitination, and pathogenic KLHL7 mutants may provide valuable information to elucidate a mechanism of retinitis pigmentosa etiology. (PMID:29032201)
• We have expanded the clinical spectrum of KLHL7 autosomal recessive variants by describing a syndrome with features overlapping CS/CISS1 and BOS. (PMID:29074562)
• KLHL7 appears to play an important role in BC progression. High KLHL7 protein expression identified a subgroup of BC with aggressive behaviour and provided independent prognostic information. (PMID:29633055)
• A novel nonsense mutation in KLHL7 was identified in two siblings with multiple dysmorphic features and developmental delay. (PMID:30300710)
• Study found novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa (PMID:31856884)
• A novel PTC mutation in the BTB domain of KLHL7 gene in two patients with Bohring-Opitz syndrome-like features. (PMID:31953236)
• Clinical and molecular genetic findings of Crisponi/cold-induced sweating syndrome (CS/CISS) spectrum in patients from Turkey. (PMID:35699517)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhl7	ENSDARG00000101445
mus_musculus	Klhl7	ENSMUSG00000028986
rattus_norvegicus	Klhl7	ENSRNOG00000010453

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL40 (ENSG00000157119), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359), KLHL33 (ENSG00000185271)

Protein

Protein identifiers

Kelch-like protein 7 — Q8IXQ5 (reviewed: Q8IXQ5)

All UniProt accessions (3): E5RFN1, Q8IXQ5, H7C259

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex. The BCR(KLHL7) complex acts by mediating ubiquitination and subsequent degradation of substrate proteins. Probably mediates ‘Lys-48’-linked ubiquitination.

Subunit / interactions. Homodimer. Component of the BCR(KLHL7) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL7 and RBX1.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Widely expressed, with highest levels in adult and fetal heart, CNS and adult testis.

Disease relevance. Perching syndrome (PERCHING) [MIM:617055] An autosomal recessive multisystem disorder characterized by global developmental delay, dysmorphic facial features, feeding and respiratory difficulties with poor overall growth, axial hypotonia, and joint contractures. The features are variable, even within families, and may also include retinitis pigmentosa, cardiac or genitourinary anomalies, and abnormal sweating. The disease is caused by variants affecting the gene represented in this entry. Retinitis pigmentosa 42 (RP42) [MIM:612943] 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. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8IXQ5-1	1	yes
Q8IXQ5-2	2
Q8IXQ5-3	3
Q8IXQ5-4	4
Q8IXQ5-5	5

RefSeq proteins (3): NP_001026880, NP_001165899, NP_061334 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR011705	BACK	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR017096	BTB-kelch_protein	Family
IPR030599	BTB/POZ_KLHL7	Domain
IPR047060	KLHL7_BACK	Domain

Pfam: PF00651, PF07707, PF24681

UniProt features (61 total): strand 28, sequence variant 10, turn 7, repeat 6, splice variant 4, sequence conflict 3, domain 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3II7	X-RAY DIFFRACTION	1.63

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IXQ5-F1	91.30	0.77

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 463 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, TGCGCANK_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, MODULE_169, BOYAULT_LIVER_CANCER_SUBCLASS_G2, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CEBPB_01, CTCTAGA_MIR526C_MIR518F_MIR526A, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_206, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, TGANTCA_AP1_C

GO Biological Process (2): protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

GO Molecular Function (4): identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (8): nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), Cul3-RING ubiquitin ligase complex (GO:0031463), perinuclear region of cytoplasm (GO:0048471), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
nuclear lumen	2
cytoplasm	2
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
enzyme-substrate adaptor activity	1
binding	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cullin-RING ubiquitin ligase complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL7	TOPORS	Q9NS56	810
KLHL7	RP9	Q8TA86	760
KLHL7	CERKL	Q49MI3	742
KLHL7	PRPF31	Q8WWY3	740
KLHL7	FSCN2	O14926	734
KLHL7	PRPF8	Q6P2Q9	734
KLHL7	SNRNP200	O75643	730
KLHL7	PRPF3	O43395	723
KLHL7	IMPDH1	P20839	720
KLHL7	ZNF513	Q8N8E2	703
KLHL7	PRCD	Q00LT1	690
KLHL7	NR2E3	Q9Y5X4	684
KLHL7	GUCA1B	Q9UMX6	682
KLHL7	IMPG2	Q9BZV3	681
KLHL7	PCARE	A6NGG8	681

IntAct

70 interactions, top by confidence:

A	B	Type	Score
CUL3	KLHL7	psi-mi:“MI:0915”(physical association)	0.830
KLHL7	CUL3	psi-mi:“MI:0403”(colocalization)	0.830
KLHL7	CUL3	psi-mi:“MI:0914”(association)	0.830
NUP50	KPNA4	psi-mi:“MI:0914”(association)	0.830
KPNA6	RNMT	psi-mi:“MI:0914”(association)	0.800
CDC23	BUB1B	psi-mi:“MI:0914”(association)	0.790
FBXL17	BACH1	psi-mi:“MI:0914”(association)	0.730
KLHL6	NUDCD3	psi-mi:“MI:0914”(association)	0.670
CARNMT1	NUP42	psi-mi:“MI:0914”(association)	0.640
STAT5A	PDHA1	psi-mi:“MI:0914”(association)	0.640
CUL3	ENC1	psi-mi:“MI:0914”(association)	0.640
SDC2	PDPK1	psi-mi:“MI:0914”(association)	0.640
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
KLHL7	KLHL7	psi-mi:“MI:0915”(physical association)	0.540
KLHL7	KLHL7	psi-mi:“MI:0403”(colocalization)	0.540
CUL3	RHOBTB1	psi-mi:“MI:0914”(association)	0.530
ARIH1	SPOP	psi-mi:“MI:0914”(association)	0.530
CUL3	ZSWIM8	psi-mi:“MI:0914”(association)	0.530
KLHL7	MICAL1	psi-mi:“MI:0915”(physical association)	0.400
KLHL7	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (75): KLHL7 (Affinity Capture-RNA), KLHL7 (Affinity Capture-RNA), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS), KLHL7 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B8YAB1, B1H285, B3DIV9, E9QIN8, E9QJ30, F1QEG2, O88879, Q08CL3, Q08CY1, Q0D2A9, Q13939, Q28068, Q3UQV5, Q3ZCT8, Q503R4, Q5F3N5, Q5R4S6, Q5R663, Q5RG82, Q5XHZ6, Q5XI58, Q5ZI33, Q69ZK5, Q6DFF7, Q6DFU2, Q6Q7X9, Q6V595, Q7ZVQ8, Q86V97, Q8BHI4, Q8BUL5, Q8BWA5, Q8CA72, Q8CDE2, Q8CE33, Q8IXQ5, Q8NAB2, Q8NFY9, Q8R179, Q8WVZ9

Diamond homologs: A0A1B8YAB1, A1YPR0, B0WWP2, B1H285, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, C9JR72, D3Z8N4, E0CZ16, G3X9X1, O15062, O88939, O93567, O95365, P28575, P41182, P41183, Q08CL3, Q08DK3, Q13105, Q16RL8, Q2M0J9, Q3UQV5, Q52KB5, Q5EXX3, Q5R7B8, Q5RDY3, Q5TC79, Q5ZI33, Q5ZKD9, Q5ZM39, Q60821

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
KLHL7	“down-regulates quantity by destabilization”	TUT1	binding
KLHL7	“up-regulates activity”	“Cullin 3-RBX1-Skp1”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
NS1 Mediated Effects on Host Pathways	5	25.5×	2e-04
ISG15 antiviral mechanism	6	16.1×	2e-04
RSV-host interactions	5	14.0×	8e-04
Mitotic Metaphase and Anaphase	5	8.6×	4e-03
Mitotic Anaphase	5	8.6×	4e-03
HCMV Early Events	5	7.2×	7e-03
Class I MHC mediated antigen processing & presentation	5	6.3×	1e-02
Viral Infection Pathways	10	5.5×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein import into nucleus	6	11.5×	4e-03
protein ubiquitination	11	6.1×	1e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — MLYM, NHL.

Clinical variants and AI predictions

ClinVar

530 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	19
Uncertain significance	257
Likely benign	173
Benign	12

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1010	NM_001031710.3(KLHL7):c.457G>A (p.Ala153Thr)	Pathogenic
1030980	NM_001031710.3(KLHL7):c.807C>A (p.Tyr269Ter)	Pathogenic
1228383	NM_001031710.3(KLHL7):c.1114C>T (p.Arg372Ter)	Pathogenic
1301555	NM_001031710.3(KLHL7):c.1229G>A (p.Trp410Ter)	Pathogenic
1384460	NM_001031710.3(KLHL7):c.617del (p.Gln206fs)	Pathogenic
1451477	NM_001031710.3(KLHL7):c.232_253dup (p.Val85delinsAlaTer)	Pathogenic
1455727	NM_001031710.3(KLHL7):c.648_657del (p.Lys216fs)	Pathogenic
1456159	NM_001031710.3(KLHL7):c.832G>T (p.Glu278Ter)	Pathogenic
1527856	NM_001031710.3(KLHL7):c.642G>C (p.Trp214Cys)	Pathogenic
1527906	NM_001031710.3(KLHL7):c.1197_1200del (p.Phe400fs)	Pathogenic
1700191	NM_001031710.3(KLHL7):c.1268A>G (p.His423Arg)	Pathogenic
2055078	NM_001031710.3(KLHL7):c.351_352del (p.Leu117fs)	Pathogenic
2110184	NM_001031710.3(KLHL7):c.1298_1299del (p.Tyr433fs)	Pathogenic
226127	NM_001031710.3(KLHL7):c.1261T>A (p.Cys421Ser)	Pathogenic
226129	NM_001031710.3(KLHL7):c.1022del (p.Leu341fs)	Pathogenic
226130	NM_001031710.3(KLHL7):c.1115G>A (p.Arg372Gln)	Pathogenic
2842530	NM_001031710.3(KLHL7):c.1382G>A (p.Trp461Ter)	Pathogenic
3245858	NC_000007.13:g.(?23191666)(23191848_?)del	Pathogenic
3615727	NM_001031710.3(KLHL7):c.690_762del (p.Ala231fs)	Pathogenic
4279705	NM_001031710.3(KLHL7):c.595_596del (p.Leu199fs)	Pathogenic
4731593	NM_001031710.3(KLHL7):c.208_218del (p.Asn70fs)	Pathogenic
804273	NM_001031710.3(KLHL7):c.1051C>T (p.Arg351Ter)	Pathogenic
816804	NM_001031710.3(KLHL7):c.565C>T (p.Arg189Ter)	Pathogenic
1228387	NM_001031710.3(KLHL7):c.223+5G>C	Likely pathogenic
1228389	NM_001031710.3(KLHL7):c.815T>C (p.Leu272Pro)	Likely pathogenic
1285582	NM_001031710.3(KLHL7):c.433A>T (p.Asn145Tyr)	Likely pathogenic
1331563	NM_001031710.3(KLHL7):c.562A>T (p.Lys188Ter)	Likely pathogenic
1341505	NM_001031710.3(KLHL7):c.944del (p.Ser315fs)	Likely pathogenic
1958241	NM_001031710.3(KLHL7):c.1178-2A>G	Likely pathogenic
2109490	NM_001031710.3(KLHL7):c.443-1G>A	Likely pathogenic

SpliceAI

3258 predictions. Top by Δscore:

Variant	Effect	Δscore
3:183491977:T:TA	donor_gain	1.0000
3:183492489:CTCA:C	donor_loss	1.0000
3:183492490:TCA:T	donor_loss	1.0000
3:183492491:CA:C	donor_loss	1.0000
3:183492492:ACCA:A	donor_loss	1.0000
3:183492493:CCAA:C	donor_gain	1.0000
3:183494278:CCAC:C	acceptor_gain	1.0000
3:183494279:CAC:C	acceptor_gain	1.0000
3:183494279:CACC:C	acceptor_gain	1.0000
3:183494280:ACCTG:A	acceptor_loss	1.0000
3:183494281:CCTG:C	acceptor_loss	1.0000
3:183494282:C:CC	acceptor_gain	1.0000
3:183494282:CT:C	acceptor_loss	1.0000
3:183494283:T:C	acceptor_loss	1.0000
3:183508054:CTCA:C	donor_loss	1.0000
3:183508055:TCA:T	donor_loss	1.0000
3:183508057:A:AC	donor_gain	1.0000
3:183508057:ACCT:A	donor_gain	1.0000
3:183508058:C:CA	donor_loss	1.0000
3:183508058:C:CC	donor_gain	1.0000
3:183508058:CCT:C	donor_gain	1.0000
3:183508058:CCTC:C	donor_gain	1.0000
3:183508082:T:TA	donor_gain	1.0000
3:183508090:T:TA	donor_gain	1.0000
3:183508517:A:AC	acceptor_gain	1.0000
3:183508517:A:C	acceptor_gain	1.0000
3:183555356:CTGA:C	donor_loss	1.0000
3:183555357:TGA:T	donor_loss	1.0000
3:183555358:GAC:G	donor_loss	1.0000
3:183555359:A:AC	donor_loss	1.0000

AlphaMissense

3881 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:23106139:G:C	R38P	1.000
7:23123841:T:A	L62H	1.000
7:23123844:C:A	A63D	1.000
7:23123852:A:C	S66R	1.000
7:23123854:T:A	S66R	1.000
7:23123854:T:G	S66R	1.000
7:23123874:T:C	F73S	1.000
7:23124757:T:C	L98P	1.000
7:23124765:T:C	F101L	1.000
7:23124767:T:A	F101L	1.000
7:23124767:T:G	F101L	1.000
7:23125083:T:C	L118P	1.000
7:23125091:G:C	A121P	1.000
7:23125092:C:A	A121E	1.000
7:23125127:T:C	C133R	1.000
7:23125128:G:A	C133Y	1.000
7:23125129:T:G	C133W	1.000
7:23125136:T:C	F136L	1.000
7:23125138:T:A	F136L	1.000
7:23125138:T:G	F136L	1.000
7:23140783:G:C	A153P	1.000
7:23143872:T:A	W214R	1.000
7:23143872:T:C	W214R	1.000
7:23143874:G:C	W214C	1.000
7:23143874:G:T	W214C	1.000
7:23143896:C:A	R222S	1.000
7:23143897:G:C	R222P	1.000
7:23143933:G:C	R234T	1.000
7:23143933:G:T	R234M	1.000
7:23152133:G:C	R287T	1.000

dbSNP variants (sampled 300 via entrez): RS1000000452 (7:23136028 G>T), RS1000016820 (7:23121395 T>C), RS1000053080 (7:23136305 A>G,T), RS1000055619 (7:23177531 A>G), RS1000089289 (7:23164390 T>C,G), RS1000107654 (7:23164656 G>A), RS1000185943 (7:23177826 A>G), RS1000195971 (7:23116622 C>T), RS1000233426 (7:23127756 C>T), RS1000239132 (7:23133672 G>A,C,T), RS1000282684 (7:23115602 G>C), RS1000286060 (7:23129776 C>A,T), RS1000404788 (7:23147011 A>G), RS1000405053 (7:23105847 C>A,T), RS1000477522 (7:23159372 G>A)

Disease associations

OMIM: gene MIM:611119 | disease phenotypes: MIM:612943, MIM:268000, MIM:617055, MIM:272430, MIM:601378, MIM:108120, MIM:605039

GenCC curated gene-disease

Disease	Classification	Inheritance
PERCHING syndrome	Definitive	Autosomal recessive
retinitis pigmentosa 42	Strong	Autosomal dominant
cold-induced sweating syndrome	Supportive	Autosomal recessive
retinitis pigmentosa	Supportive	Autosomal dominant

Mondo (8): retinitis pigmentosa 42 (MONDO:0013052), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), PERCHING syndrome (MONDO:0014890), Cold-induced sweating syndrome 1 (MONDO:0010091), distal arthrogryposis (MONDO:0019942), Bohring-Opitz syndrome (MONDO:0011510), cold-induced sweating syndrome (MONDO:0015526)

Orphanet (7): Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Cold-induced sweating syndrome (Orphanet:157820), KLHL7-related Bohring-Opitz-like and Crisponi/Cold-induced sweating-like overlap syndrome (Orphanet:603684), Crisponi syndrome (Orphanet:1545), Distal arthrogryposis (Orphanet:97120), Bohring-Opitz syndrome (Orphanet:97297)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000293	Full cheeks
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000842	Hyperinsulinemia
HP:0000961	Cyanosis
HP:0001105	Retinal atrophy
HP:0001249	Intellectual disability
HP:0001945	Fever
HP:0002015	Dysphagia
HP:0002098	Respiratory distress
HP:0002650	Scoliosis
HP:0003593	Infantile onset
HP:0003596	Middle age onset

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002750_1	Chronic obstructive pulmonary disease	6.000000e-08
GCST003984_23	Parkinson’s disease	2.000000e-12
GCST004902_50	Parkinson’s disease	4.000000e-18
GCST010991_3	Parkinson’s disease	8.000000e-12
GCST011011_26	Youthful appearance (self-reported)	3.000000e-09

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C537419	Bohring syndrome (supp.)
C536214	Crisponi syndrome (supp.)
C567854	Retinitis Pigmentosa 42 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196109 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases methylation, affects expression	4
Cisplatin	affects expression, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
cobaltous chloride	affects cotreatment, increases expression	2
Hydrogen Peroxide	affects cotreatment, decreases expression, increases expression, affects expression	2
Cyclosporine	decreases methylation, increases expression	2
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression	1
periodate-oxidized adenosine	affects expression	1
lead chloride	affects cotreatment, increases expression	1
cadmium sulfate	increases expression, affects cotreatment	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Air Pollutants	decreases expression, increases abundance	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Fluorouracil	affects response to substance	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	decreases expression	1
Theophylline	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6094266	Binding	Binding affinity to KLHL7 (unknown origin) at 10 uM by thermal shift assay	Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors. — J Med Chem

Clinical trials (associated diseases)

259 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa