CRLF1

protein-coding

cytokine receptor like factor 1, the group of Fibronectin type III domain containing

Gene summary

This gene encodes a member of the cytokine type I receptor family. The protein forms a secreted complex with cardiotrophin-like cytokine factor 1 and acts on cells expressing ciliary neurotrophic factor receptors. The complex can promote survival of neuronal cells. Mutations in this gene result in Crisponi syndrome and cold-induced sweating syndrome. [provided by RefSeq, Oct 2009]

MANE transcript

NM_004750.5

Inheritance

ClinVar variants

P:34U:96B:73

Top phenotype

Crisponi/Cold-induced sweating syndrome, type 1

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr19:18,572,220-18,607,741

External References & Databases

Ensembl (ENSG00000006016)

Transcript & Mutation Effects

hg38 • Region Span ~35.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

idiopathic achalasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019635

Submitter: Orphanet

Cold-induced sweating syndrome 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010091

Submitter: Orphanet

Cold-induced sweating syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010091

Submitter: G2P

cold-induced sweating syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015526

Submitter: Orphanet

Cold-induced sweating syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010091

Submitter: Labcorp Genetics (formerly Invitae)

Cold-induced sweating syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010091

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Crisponi/Cold-induced sweating syndrome, type 1AR

Manifestation: Musculoskeletal; Neurologic

Intervention: Neurologic

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: 8723066; 12509788; 17436252; 17436251; 18837055; 19012339; 20186812; 20400119; 21326283; 21370513; 23026229

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CRLF1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 137

Inborn genetic diseasesTotal: 65

Cold-induced sweating syndrome 1Total: 32

not specifiedTotal: 30

Cold-induced sweating syndromeTotal: 5

CRLF1-related disorderTotal: 5

Cone-rod dystrophy 12Total: 1

Crisponi/Cold-induced sweating syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004750.5. 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	65 clinvar	1 clinvar	67
missense	1 clinvar	5 clinvar	92 clinvar	7 clinvar		105
nonsense	6 clinvar					6
start loss		2 clinvar				2
frameshift	13 clinvar	4 clinvar	1 clinvar			18
splice donor/acceptor (+/-2bp)		3 clinvar	2 clinvar			5
Total	20	14	96	72	1	203

Highest pathogenic variant AF is 0.00003534958

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004750.5	RefSeq	NP_004741.1	9	MANE Select
ENST00000392386.8	Ensembl	ENSP00000376188.2	9	MANE Select
ENST00000597131.1	Ensembl	ENSP00000470625.1	4	Standard
ENST00000684169.1	Ensembl	ENSP00000506849.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

JAK-STAT-Core
Signaling by Interleukins
IL-6-type cytokine receptor ligand interactions
Cytokine Signaling in Immune system
Immune System

Biological Process

ureteric bud development
positive regulation of cell population proliferation
regulation of signaling receptor activity
cytokine-mediated signaling pathway
positive regulation of tyrosine phosphorylation of STAT protein

Molecular Function

cytokine receptor activity
cytokine activity
ciliary neurotrophic factor receptor binding
protein binding
cytokine binding

Cellular Component

extracellular region
extracellular space
cytosol
external side of plasma membrane
receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392386
Coding exons: 9
Length: 35522
Individuals with no LoFs: 125690
Homozygous LoFs: 0
Heterozygous LoFs: 54
Defined: 125744
p: 0.000215

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.475	224	245	0.915	0.0000150	2656
Missense (PolyPhen)		92	96.912	0.94931		1035
Synonymous	0.193	109	112	0.977	0.00000725	908
Loss of Function	1.86	10	18.7	0.535	8.10e-7	213

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00047	0.00046	rare
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.00027	0.00027	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00014	0.00013	rare
South Asian	0.00013	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cytokine receptor subunit, possibly playing a regulatory role in the immune system and during fetal development. May be involved in nervous system development.;
Disease: DISEASE: Crisponi/Cold-induced sweating syndrome 1 (CISS1) [MIM:272430]: An autosomal recessive disorder characterized by profuse sweating induced by cool surroundings (temperatures of 7 to 18 degrees Celsius). Patients manifest, in the neonatal period, orofacial weakness with impaired sucking and swallowing, resulting in poor feeding. Affected infants show a tendency to startle, with contractions of the facial muscles in response to tactile stimuli or during crying, trismus, abundant salivation, and opisthotonus. These features are referred to as Crisponi syndrome and can result in early death in infancy. Patients who survive into childhood have hyperhidrosis, mainly of the upper body, in response to cold temperatures, and sweat very little with heat. Additional abnormalities include a high-arched palate, nasal voice, depressed nasal bridge, inability to fully extend the elbows and kyphoscoliosis. {ECO:0000269|PubMed:12509788, ECO:0000269|PubMed:16952376, ECO:0000269|PubMed:17436251, ECO:0000269|PubMed:17436252, ECO:0000269|PubMed:21326283, ECO:0000269|PubMed:23026229, ECO:0000269|PubMed:24488861}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.198

Intolerance Scores

LoFtool: 0.328
RVIS EVS: -0.65
RVIS percentile EVS: 16.36

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.982

Gene Damage Prediction

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