KLHL7

Chr 7ARAD

kelch like family member 7

Also known as: CISS3, KLHL6, PERCHING, SBBI26

NCBI Gene: 55975ENSG00000122550UniProt: Q8IXQ5

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. [provided by RefSeq, Feb 2010]

Primary Disease Associations & Inheritance

PERCHING syndromeMIM #617055
AR
Retinitis pigmentosa 42MIM #612943
AD
0
Active trials
42
Pathogenic / LP
392
ClinVar variants
3
Pubs (1 yr)
3.9
Missense Z· constrained
0.64
LOEUF
Clinical Summary— KLHL7
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
42 Pathogenic / Likely Pathogenic· 182 VUS of 392 total submissions
📖
GeneReview available — KLHL7
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint
0.64LOEUF
pLI 0.000
Z-score 3.13
OE 0.40 (0.26–0.64)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
3.91Z-score
OE missense 0.38 (0.33–0.45)
123 obs / 319.5 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.40 (0.26–0.64)
0≤0.351.4
Missense OE0.38 (0.33–0.45)
0≤0.61.4
Synonymous OE0.90
0≤1.21.6
LoF obs/exp: 13 / 32.1Missense obs/exp: 123 / 319.5Syn Z: 0.84
DNGOF
DN
0.6937th %ile
GOF
0.6639th %ile
LOF
0.2871th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNTogether, our results suggest that KLHL7 constitutes a Cul3-based E3 and that the disease-causing mutation inhibits ligase activity in a dominant negative manner, which may lead to the inappropriate accumulation of the substrates targeted for proteasomal degradation.PMID:21828050

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

392 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic20
VUS182
Likely Benign157
Benign3
Conflicting8
22
Pathogenic
20
Likely Pathogenic
182
VUS
157
Likely Benign
3
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
2
12
0
22
Likely Pathogenic
8
5
7
0
20
VUS
0
152
26
4
182
Likely Benign
0
0
52
105
157
Benign
0
0
2
1
3
Conflicting
—8
Total1615999110392

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

KLHL7 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

KLHL7-related PERCHING syndrome (developmental delay, dysmorphism, feeding and respiratory difficulties, hypotonia, and joint contractures)

strong
ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. DisordersEye
G2P ↗
frameshift variantmissense variant

KLHL7-related retinitis pigmentosa

strong
ADUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients