FHL1

Chr XARXLRXLDX-linked

complement factor H

Also known as: AHUS1, AMBP1, ARMD4, ARMS1, CFHL3, FH, FHL1, HF

NCBI Gene: 3075 ENSG00000022267 UniProt: Q13642

This gene is a member of the Regulator of Complement Activation (RCA) gene cluster and encodes a protein with twenty short consensus repeat (SCR) domains. This protein is secreted into the bloodstream and has an essential role in the regulation of complement activation, restricting this innate defense mechanism to microbial infections. Mutations in this gene have been associated with hemolytic-uremic syndrome (HUS) and chronic hypocomplementemic nephropathy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Oct 2011]

Primary Disease Associations & Inheritance

Hemophagocytic lymphohistiocytosis, familial, 1MIM #267700

?Uruguay faciocardiomusculoskeletal syndromeMIM #300280

XLR

Emery-Dreifuss muscular dystrophy 6, X-linkedMIM #300696

XLR

Myopathy, X-linked, with postural muscle atrophyMIM #300696

XLR

Reducing body myopathy, X-linked 1a, severe, infantile or early childhood onsetMIM #300717

XLD

Reducing body myopathy, X-linked 1b, with late childhood or adult onsetMIM #300718

X-linked

Scapuloperoneal myopathy, X-linked dominantMIM #300695

XLD

845

ClinVar variants

100

Pathogenic / LP

0.97

pLI score· haploinsufficient

Active trials

Clinical Summary— FHL1

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

100 Pathogenic / Likely Pathogenic· 195 VUS of 845 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.28LOEUF

pLI 0.970

Z-score 3.05

OE 0.00 (0.00–0.28)

Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.89Z-score

OE missense 0.78 (0.67–0.92)

105 obs / 134.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.28)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.67–0.92)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.77

0≤1.21.6

LoF obs/exp: 0 / 10.8Missense obs/exp: 105 / 134.0Syn Z: 1.32

ClinVar Variant Classifications

845 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic78

Likely Pathogenic22

VUS195

Likely Benign115

Benign12

Conflicting13

Pathogenic

Likely Pathogenic

195

VUS

115

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	28	6	44	0	78
Likely Pathogenic	6	9	7	0	22
VUS	6	168	19	2	195
Likely Benign	1	8	49	57	115
Benign	0	0	12	0	12
Conflicting	—				13
Total	41	191	131	59	435

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

View in ClinVar →

Protein Context — Lollipop Plot

FHL1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

FHL1-related Emery-Dreifuss muscular dystrophy

definitive

Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure, Decreased Gene Product Level

Dev. DisordersCardiac

G2P ↗

splice region variantstop lostmissense variantstop gained NMD escapingframeshift variant NMD escaping

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

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 1; FHL1

MIM #267700 · %

Hemophagocytic lymphohistiocytosis, familial, 1

MIM #267700

Disorder mapped to chromosomal region

Autosomal recessive

FOUR-AND-A-HALF LIM DOMAINS 1; FHL1

MIM #300163 · *

?Uruguay faciocardiomusculoskeletal syndrome

MIM #300280