KLHL7

protein-coding

kelch like family member 7, the group of Kelch like|BTB domain containing

Gene summary

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]

MANE transcript

NM_001031710.3

Inheritance

AD, AR

ClinVar variants

P:52U:189B:126

Top phenotype

Perching syndrome (Crisponi/Cold-induced sweating syndrome 3)

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr7:23,105,758-23,177,914

External References & Databases

Ensembl (ENSG00000122550)

Transcript & Mutation Effects

hg38 • Region Span ~72.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

cold-induced sweating syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015526

Submitter: Orphanet

retinitis pigmentosa 42STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013052

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa 42STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013052

Submitter: G2P

retinitis pigmentosa 42STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013052

Submitter: PanelApp Australia

PERCHING syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014890

Submitter: PanelApp Australia

retinitis pigmentosa 42MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013052

Submitter: Ambry Genetics

PERCHING syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014890

Submitter: Ambry Genetics

PERCHING syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014890

Submitter: Illumina

PERCHING syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014890

Submitter: G2P

Clinical Genomic Database (CGD)

Perching syndrome (Crisponi/Cold-induced sweating syndrome 3)AR

Manifestation: Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Musculoskeletal

Rationale: In the neonatal/early childhood period, the condition can be lethal unless advanced care is instituted; Later, it has been described that cold-induced sweating was alleviated by medical treatment (eg, with clonidine)

Refs: 1872134; 19520207; 20547956; 22084217; 27392078

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KLHL7 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 367

not specifiedTotal: 61

KLHL7-related disorderTotal: 53

Inborn genetic diseasesTotal: 37

PERCHING syndromeTotal: 27

Retinitis pigmentosaTotal: 17

Retinitis pigmentosa 42Total: 13

Retinal dystrophyTotal: 13

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001031710.3. 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			5 clinvar	122 clinvar	2 clinvar	129
missense	4 clinvar	11 clinvar	177 clinvar	2 clinvar		194
nonsense	8 clinvar	2 clinvar	4 clinvar			14
start loss						0
frameshift	11 clinvar	8 clinvar	1 clinvar			20
splice donor/acceptor (+/-2bp)		8 clinvar	2 clinvar			10
Total	23	29	189	124	2	367

Highest pathogenic variant AF is 0.000025433297

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 66 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001031710.3	RefSeq	NP_001026880.2	11	MANE Select
ENST00000339077.10	Ensembl	ENSP00000343273.4	11	MANE Select
NM_001172428.2	RefSeq	NP_001165899.1	5	Standard
NM_018846.5	RefSeq	NP_061334.4	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein ubiquitination

Molecular Function

protein binding
identical protein binding
protein homodimerization activity

Cellular Component

nucleus
nucleoplasm
nucleolus
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000339077
Coding exons: 11
Length: 72181
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 35
Defined: 125748
p: 0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.91	123	320	0.385	0.0000166	3872
Missense (PolyPhen)		29	87.734	0.33054		998
Synonymous	0.837	101	112	0.899	0.00000620	1089
Loss of Function	3.13	13	32.1	0.404	0.00000196	357

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00028	0.00028	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: 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. {ECO:0000269|PubMed:21828050}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:19520207, ECO:0000269|PubMed:20547956, ECO:0000269|PubMed:21828050, ECO:0000269|PubMed:22084217}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.122

Intolerance Scores

LoFtool: 0.646
RVIS EVS: -0.76
RVIS percentile EVS: 13.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.296

Gene Damage Prediction

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