CLCF1

Chr 11AR

cardiotrophin like cytokine factor 1

Also known as: BSF-3, BSF3, CISS2, CLC, NNT-1, NNT1, NR6

NCBI Gene: 23529 ENSG00000175505 UniProt: Q9UBD9 OMIM: 607672

CLCF1 encodes cardiotrophin-like cytokine factor 1, which forms a heterodimeric neurotropic cytokine complex with CRLF1 that plays a crucial role in neuronal development and also stimulates B-cells by activating the gp130 receptor and Jak-STAT signaling pathway. Mutations cause cold-induced sweating syndrome 2, an autosomal recessive disorder characterized by profuse sweating after cold exposure along with congenital abnormalities of the head and spine. This condition typically presents in infancy with the distinctive cold-induced sweating response and associated craniofacial and spinal malformations.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of the glycoprotein (gp)130 cytokine family and encodes cardiotrophin-like cytokine factor 1 (CLCF1). CLCF1 forms a heterodimer complex with cytokine receptor-like factor 1 (CRLF1). This dimer competes with ciliary neurotrophic factor (CNTF) for binding to the ciliary neurotrophic factor receptor (CNTFR) complex, and activates the Jak-STAT signaling cascade. CLCF1 can be actively secreted from cells by forming a complex with soluble type I CRLF1 or soluble CNTFR. CLCF1 is a potent neurotrophic factor, B-cell stimulatory agent and neuroendocrine modulator of pituitary corticotroph function. Defects in CLCF1 cause cold-induced sweating syndrome 2 (CISS2). This syndrome is characterized by a profuse sweating after exposure to cold as well as congenital physical abnormalities of the head and spine. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

ARLOEUF 0.321 OMIM phenotype

Clinical Summary— CLCF1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 43 VUS of 71 total submissions

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GeneReview available — CLCF1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.948

Z-score 2.83

OE 0.00 (0.00–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.12Z-score

OE missense 0.74 (0.63–0.86)

104 obs / 141.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.32)

0≤0.351.4

Missense OE?0.74 (0.63–0.86)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 0 / 9.3Missense obs/exp: 104 / 141.5Syn Z: 0.41

ClinVar Variant Classifications

71 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

VUS43

Likely Benign15

Benign4

Conflicting1

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	2	0	0	4
Likely Pathogenic	0	0	0	0	0
VUS	0	42	1	0	43
Likely Benign	0	2	1	12	15
Benign	1	1	1	1	4
Conflicting	—				1
Total	3	47	3	13	67

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

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12 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap CLCF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →