FHL1

Chr XARXLRXLDX-linked

four and a half LIM domains 1

Also known as: FCMSU, FHL-1, FHL1A, FHL1B, FLH1A, KYOT, RBMX1A, RBMX1B

NCBI Gene: 2273 ENSG00000022267 UniProt: Q13642 OMIM: 267700

The FHL1 protein is a member of the four-and-a-half-LIM-only protein family containing zinc finger domains that function in various cellular processes. Mutations cause a spectrum of X-linked muscle disorders including Emery-Dreifuss muscular dystrophy, reducing body myopathy, scapuloperoneal myopathy, and myopathy with postural muscle atrophy, as well as autosomal recessive familial hemophagocytic lymphohistiocytosis. The pathogenic mechanism involves loss of function of this cytoplasmic protein.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismAR/XLR/XLD/X-linkedLOEUF 0.287 OMIM phenotypes

Clinical Summary— FHL1

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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

43 unique Pathogenic / Likely Pathogenic· 69 VUS of 200 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FHL1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

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

0.89Z-score

OE missense 0.78 (0.67–0.92)

105 obs / 134.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.00 (0.00–0.28)

0≤0.351.4

Missense OE0.78 (0.67–0.92)

0≤0.61.4

Synonymous OE0.77

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFHL1-related Emery-Dreifuss muscular dystrophyLOFXLR

0.4289th %ile

GOF

0.4480th %ile

LOF

0.70top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 53% of P/LP variants are LoF · LOEUF 0.28

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38

Likely Pathogenic5

VUS69

Likely Benign86

Benign1

Conflicting1

Pathogenic

Likely 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	21	1	16	0	38
Likely Pathogenic	2	2	1	0	5
VUS	2	57	9	1	69
Likely Benign	0	6	38	42	86
Benign	0	0	1	0	1
Conflicting	—				1
Total	25	66	65	43	200

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.

3D Protein StructureAlphaFold

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — FHL1

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Mild Cognitive ImpairmentAlzheimer's DiseaseAlzheimer's Disease, Early Onset

Development of a Database to Investigate Digital and Blood-Based Biomarkers and Their Relationship to Tau and Amyloid PET Imaging in Older Participants Who Are Cognitively Normal (CN), Have Mild Cognitive Impairment (MCI), or Have Mild-to-Moderate AD Dementia

RECRUITING

NCT06584357GAP Innovations, PBCStarted 2024-09-26

Biomarker Data CollectionMK6240

Meningococcal Meningitis, Serogroup BTransgender PersonsSex Differences in Immune Response

Investigating Gender and Sex Differences in Immune Responses Through Vaccination of Transgender and Cisgender Persons

RECRUITING

NCT06832514Phase PHASE4University GhentStarted 2025-01-31

Serogroup B meningococal vaccine

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

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