CRLF1

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

Basic information

Region (hg38): 19:18572219-18607741

Links

ENSG00000006016 ∙ NCBI:9244 ∙ OMIM:604237 ∙ HGNC:2364 ∙ Uniprot:O75462 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Cold-induced sweating syndrome 1 (Definitive), mode of inheritance: AR
• idiopathic achalasia (Supportive), mode of inheritance: AR
• Cold-induced sweating syndrome 1 (Supportive), mode of inheritance: AR
• cold-induced sweating syndrome (Supportive), mode of inheritance: AR
• Cold-induced sweating syndrome 1 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Crisponi/Cold-induced sweating syndrome, type 1	AR	Neurologic	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)	Musculoskeletal; Neurologic	8723066; 12509788; 17436252; 17436251; 18837055; 19012339; 20186812; 20400119; 21326283; 21370513; 23026229

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CRLF1 gene.

• not provided (98 variants)
• Inborn genetic diseases (15 variants)
• Cold-induced sweating syndrome 1 (10 variants)
• not specified (8 variants)
• Cold-induced sweating syndrome (3 variants)
• Cone-rod dystrophy 12 (1 variants)
• Crisponi/Cold-induced sweating syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CRLF1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				32	4	36
missense		2	39	1	1	43
nonsense	4					4
start loss		1				1
frameshift	4	1	1			6
inframe indel			1	1	1	3
splice donor/acceptor (+/-2bp)		1				1
splice region			2	3		5
non coding				7	14	21
Total	8	5	41	41	20

Highest pathogenic variant AF is 0.0000657

Variants in CRLF1

This is a list of pathogenic ClinVar variants found in the CRLF1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-18573368-T-C		not specified	Uncertain significance (Dec 20, 2022)
19-18573706-C-G		not specified	Uncertain significance (Aug 08, 2022)
19-18588898-T-G		not specified	Uncertain significance (Oct 06, 2021)
19-18589641-C-G		not specified	Uncertain significance (Oct 29, 2021)
19-18593575-A-G			Benign (Dec 21, 2023)
19-18593718-C-T			Benign (May 10, 2021)
19-18594033-C-T			Benign (May 23, 2021)
19-18594073-G-C		Inborn genetic diseases	Uncertain significance (Jun 29, 2021)
19-18594087-C-T			Likely benign (Mar 15, 2022)
19-18594126-CAG-C			Likely benign (Nov 27, 2023)
19-18594230-G-A		not specified	Benign/Likely benign (Jan 13, 2024)
19-18594238-C-T			Likely benign (Aug 17, 2022)
19-18594255-G-A			Uncertain significance (Jul 23, 2022)
19-18594256-G-A			Likely benign (Aug 17, 2023)
19-18594265-C-A			Likely benign (Nov 27, 2023)
19-18594316-G-A			Likely benign (Apr 10, 2018)
19-18594323-T-TA			Uncertain significance (Dec 22, 2022)
19-18594338-A-C		Cold-induced sweating syndrome 1	not provided (-)
19-18594357-T-A		Cold-induced sweating syndrome 1	Pathogenic (May 01, 2007)
19-18594367-C-T			Benign/Likely benign (Jan 18, 2024)
19-18594372-C-T		Inborn genetic diseases	Uncertain significance (Jun 28, 2022)
19-18594379-C-G			Likely benign (Sep 04, 2022)
19-18594394-G-A		CRLF1-related disorder	Likely benign (Aug 29, 2022)
19-18594395-C-A		Inborn genetic diseases	Uncertain significance (Jul 31, 2023)
19-18594422-G-C		Inborn genetic diseases	Uncertain significance (May 31, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CRLF1	protein_coding	protein_coding	ENST00000392386	9	35522

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000400	0.959	125690	0	54	125744	0.000215

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.475	224	245	0.915	0.0000150	2656
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000773	0.000773
Ashkenazi Jewish	0.000499	0.000496
East Asian	0.000275	0.000272
Finnish	0.0000929	0.0000924
European (Non-Finnish)	0.000136	0.000132
Middle Eastern	0.000275	0.000272
South Asian	0.000132	0.000131
Other	0.000326	0.000326

dbNSFP

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.
• Pathway: JAK-STAT-Core;Signaling by Interleukins;IL-6-type cytokine receptor ligand interactions;Cytokine Signaling in Immune system;Immune System;Interleukin-6 family signaling (Consensus)

Recessive Scores

• pRec: 0.198

Intolerance Scores

• loftool: 0.328
• rvis_EVS: -0.65
• rvis_percentile_EVS: 16.36

Haploinsufficiency Scores

• pHI: 0.447
• hipred: N
• hipred_score: 0.485
• ghis: 0.604

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.982

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Crlf1
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• 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;negative regulation of neuron apoptotic process;interleukin-27-mediated signaling pathway;negative regulation of motor neuron apoptotic process
• Cellular component: extracellular region;extracellular space;cytosol;external side of plasma membrane;receptor complex;CRLF-CLCF1 complex
• Molecular function: cytokine receptor activity;cytokine activity;ciliary neurotrophic factor receptor binding;protein binding;cytokine binding;protein heterodimerization activity