FHL1

four and a half LIM domains 1, the group of LIM domain containing

Basic information

Region (hg38): X:136146701-136211359

Links

ENSG00000022267 ∙ NCBI:2273 ∙ OMIM:300163 ∙ HGNC:3702 ∙ Uniprot:Q13642 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• X-linked myopathy with postural muscle atrophy (Definitive), mode of inheritance: XLR
• reducing body myopathy (Supportive), mode of inheritance: XL
• X-linked Emery-Dreifuss muscular dystrophy (Supportive), mode of inheritance: XL
• X-linked myopathy with postural muscle atrophy (Supportive), mode of inheritance: XL
• X-linked scapuloperoneal muscular dystrophy (Supportive), mode of inheritance: XL
• X-linked Emery-Dreifuss muscular dystrophy (Definitive), mode of inheritance: AD
• X-linked myopathy with postural muscle atrophy (Definitive), mode of inheritance: XL
• myopathy, reducing body, X-linked, early-onset, severe (Strong), mode of inheritance: XL
• X-linked myopathy with postural muscle atrophy (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Reducing body myopathy, X-linked 1A, with infantile or early childhood onset; Reducing body myopathy, X-linked 1B, with late childhood or adult onset; Emery-Dreifuss muscular dystrophy 6, X-linked; Myopathy, X-linked, with postural muscle atrophy; Uruguay faciocardiomusculoskeletal syndrome	XL	Cardiovascular	Surveillance for cardiovascular disease (eg, cardiomyopathy, arrhythmias) and early medical treatment may reduce morbidity	Cardiovascular; Musculoskeletal	4250729; 7722535; 8619529; 11102932; 16919903; 18179901; 18952429; 18274675; 18179888; 19716112; 19181672; 19687455; 19171836; 20186852; 26933038
In reducing body myopathy, dilated cardiomyopathy has been described, but well after clinical onset; In Myopathy with postural muscle atrophy and Emery-Dreifuss muscular dystrophy 6, heart failure can be deadly, perhaps related to hypertrophic cardiomyopathy; In Emery-Dreifuss muscular dystrophy 6, arrhythmias have been desribed, as well as sudden cardiac death; In all situations, survelliance and early medical management could be beneficial, but the condition may not be easily clinically recognizable

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FHL1 gene.

• X-linked myopathy with postural muscle atrophy (321 variants)
• not provided (124 variants)
• Cardiovascular phenotype (72 variants)
• not specified (39 variants)
• Inborn genetic diseases (5 variants)
• Uruguay Faciocardiomusculoskeletal syndrome;X-linked scapuloperoneal muscular dystrophy;Myopathy, reducing body, X-linked, childhood-onset;Myopathy, reducing body, X-linked, early-onset, severe;X-linked myopathy with postural muscle atrophy (5 variants)
• Myopathy, reducing body, X-linked, early-onset, severe (4 variants)
• Myopathy, reducing body, X-linked, childhood-onset;Myopathy, reducing body, X-linked, early-onset, severe;X-linked myopathy with postural muscle atrophy;Uruguay Faciocardiomusculoskeletal syndrome;X-linked scapuloperoneal muscular dystrophy (3 variants)
• X-linked scapuloperoneal muscular dystrophy (3 variants)
• Uruguay Faciocardiomusculoskeletal syndrome (3 variants)
• Myopathy, reducing body, X-linked, childhood-onset (3 variants)
• Primary familial hypertrophic cardiomyopathy (3 variants)
• Abnormality of the musculature (2 variants)
• Emery-Dreifuss muscular dystrophy 6 (1 variants)
• X-linked myopathy with postural muscle atrophy;X-linked scapuloperoneal muscular dystrophy (1 variants)
• Uruguay Faciocardiomusculoskeletal syndrome;Myopathy, reducing body, X-linked, childhood-onset;Myopathy, reducing body, X-linked, early-onset, severe;X-linked myopathy with postural muscle atrophy;X-linked scapuloperoneal muscular dystrophy (1 variants)
• FHL1-related condition (1 variants)
• FHL1-related disorders (1 variants)
• Uruguay Faciocardiomusculoskeletal syndrome;X-linked scapuloperoneal muscular dystrophy;Myopathy, reducing body, X-linked, early-onset, severe;Myopathy, reducing body, X-linked, childhood-onset;X-linked myopathy with postural muscle atrophy (1 variants)
• X-linked scapuloperoneal muscular dystrophy;Uruguay Faciocardiomusculoskeletal syndrome;Myopathy, reducing body, X-linked, early-onset, severe;Myopathy, reducing body, X-linked, childhood-onset;X-linked myopathy with postural muscle atrophy (1 variants)
• Myopathy, reducing body, X-linked, early-onset, severe;Uruguay Faciocardiomusculoskeletal syndrome;X-linked scapuloperoneal muscular dystrophy;Myopathy, reducing body, X-linked, childhood-onset;X-linked myopathy with postural muscle atrophy (1 variants)
• Myopathy, reducing body, X-linked, early-onset, severe;Myopathy, reducing body, X-linked, childhood-onset;X-linked myopathy with postural muscle atrophy;Uruguay Faciocardiomusculoskeletal syndrome;X-linked scapuloperoneal muscular dystrophy (1 variants)
• Myopathy, reducing body, X-linked, childhood-onset;Uruguay Faciocardiomusculoskeletal syndrome;X-linked scapuloperoneal muscular dystrophy;X-linked myopathy with postural muscle atrophy;Myopathy, reducing body, X-linked, early-onset, severe (1 variants)
• Muscle weakness (1 variants)
• Myopathy, reducing body, X-linked, childhood-onset;X-linked myopathy with postural muscle atrophy;Myopathy, reducing body, X-linked, early-onset, severe;Uruguay Faciocardiomusculoskeletal syndrome;X-linked scapuloperoneal muscular dystrophy (1 variants)
• X-linked myopathy with postural muscle atrophy;Myopathy, reducing body, X-linked, childhood-onset;Myopathy, reducing body, X-linked, early-onset, severe;Uruguay Faciocardiomusculoskeletal syndrome;X-linked scapuloperoneal muscular dystrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FHL1 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				64	1	65
missense	10	7	151	9	1	178
nonsense	11	3				14
start loss			1			1
frameshift	22	6	2			30
inframe indel			6			6
splice donor/acceptor (+/-2bp)	2	4	1			7
splice region			8	18	3	29
non coding			3	38	11	52
Total	45	20	164	111	13

Highest pathogenic variant AF is 0.00000895

Variants in FHL1

This is a list of pathogenic ClinVar variants found in the FHL1 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-136147468-A-C			Benign (Jun 23, 2018)
X-136147571-C-T			Benign (Jun 25, 2020)
X-136147620-C-A		not specified	Likely benign (Oct 06, 2017)
X-136147621-C-T		not specified	Likely benign (Feb 07, 2018)
X-136147631-A-G		X-linked myopathy with postural muscle atrophy;Myopathy, reducing body, X-linked, childhood-onset;Myopathy, reducing body, X-linked, early-onset, severe;Uruguay Faciocardiomusculoskeletal syndrome;X-linked scapuloperoneal muscular dystrophy	Uncertain significance (Jul 15, 2021)
X-136147638-C-G		not specified	Likely benign (Dec 13, 2017)
X-136147722-C-G			Likely benign (Jun 21, 2019)
X-136169520-G-GA			Benign (Apr 08, 2019)
X-136169974-G-C			Likely benign (Apr 03, 2018)
X-136169997-G-T		not specified	Likely benign (Jan 30, 2017)
X-136170075-AC-A			Benign (Jul 08, 2021)
X-136196836-C-T			Uncertain significance (May 01, 2022)
X-136196860-G-A		FHL1-related disorder	Benign/Likely benign (Apr 27, 2021)
X-136196863-G-T		FHL1-related disorder	Likely benign (Oct 31, 2022)
X-136197103-T-G		FHL1-related disorder	Likely benign (Oct 11, 2022)
X-136197115-G-A			Uncertain significance (Nov 05, 2019)
X-136197128-CA-AC			Uncertain significance (Jun 01, 2022)
X-136197134-G-A		Uruguay Faciocardiomusculoskeletal syndrome	Uncertain significance (Oct 16, 2022)
X-136206125-A-G			Benign (Jun 18, 2018)
X-136206155-C-T			Likely benign (Jun 26, 2018)
X-136206402-C-T		not specified	Benign (Oct 04, 2016)
X-136206413-C-G		X-linked scapuloperoneal muscular dystrophy	Uncertain significance (-)
X-136206434-T-C		X-linked myopathy with postural muscle atrophy	Likely pathogenic (May 01, 2023)
X-136206437-C-T		X-linked myopathy with postural muscle atrophy • Cardiovascular phenotype	Conflicting classifications of pathogenicity (Feb 01, 2024)
X-136206438-G-A		Cardiovascular phenotype • X-linked myopathy with postural muscle atrophy	Likely benign (Apr 04, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FHL1	protein_coding	protein_coding	ENST00000394155	6	63960

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.970	0.0302	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.890	105	134	0.784	0.0000108	2144
Missense in Polyphen		27	45.938	0.58774		803
Synonymous	1.32	40	52.1	0.767	0.00000445	586
Loss of Function	3.05	0	10.8	0.00	7.62e-7	196

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May have an involvement in muscle development or hypertrophy.
• Disease: DISEASE: Emery-Dreifuss muscular dystrophy 6, X-linked (EDMD6) [MIM:300696]: A form of Emery-Dreifuss muscular dystrophy, a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system, early contractures of the elbows, Achilles tendons and spine, and cardiomyopathy associated with cardiac conduction defects. {ECO:0000269|PubMed:19716112, ECO:0000269|PubMed:20186852}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry.; DISEASE: Scapuloperoneal myopathy, X-linked dominant (SPM) [MIM:300695]: A disease characterized by progressive muscle weakness and wasting, upper and lower limbs weakness, foot drop, scapular winging, and myopathic changes on muscle biopsy. Most affected individuals become wheelchair-bound. {ECO:0000269|PubMed:18179901, ECO:0000269|PubMed:27234031}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, X-linked, with postural muscle atrophy (XMPMA) [MIM:300696]: A progressive muscular dystrophy with onset in adulthood. Affected individuals develop a proximal myopathy characterized by specific atrophy of postural muscles, limited neck flexion, bent spine, contractures of the Achilles tendon, respiratory problems, and cardiomyopathy. Patients may show muscle hypertrophy in the early stages of the disorder. {ECO:0000269|PubMed:18179888, ECO:0000269|PubMed:19687455}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Reducing body myopathy, X-linked 1A, severe, with infantile or early childhood onset (RBMX1A) [MIM:300717]: A rare myopathy clinically characterized by rapidly progressive muscular weakness, and pathologically by the presence of intracytoplasmic inclusion bodies strongly stained by menadione-linked alpha- glycerophosphate dehydrogenase in the absence of substrate, alpha- glycerophosphate. The term 'reducing body' refers to the reducing activity of the inclusions to nitroblue tetrazolium in the absence of substrate. This condition is also commonly associated with rimmed vacuoles and cytoplasmic bodies. Death in childhood is frequent in the severe form of the disease, due to respiratory failure. {ECO:0000269|PubMed:18274675, ECO:0000269|PubMed:19171836, ECO:0000269|PubMed:19181672}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Reducing body myopathy, X-linked 1B, with late childhood or adult onset (RBMX1B) [MIM:300718]: A rare myopathy clinically characterized by rapidly progressive muscular weakness, and pathologically by the presence of intracytoplasmic inclusion bodies strongly stained by menadione-linked alpha-glycerophosphate dehydrogenase in the absence of substrate, alpha-glycerophosphate. The term 'reducing body' refers to the reducing activity of the inclusions to nitroblue tetrazolium in the absence of substrate. This condition is also commonly associated with rimmed vacuoles and cytoplasmic bodies. {ECO:0000269|PubMed:18274675, ECO:0000269|PubMed:19171836, ECO:0000269|PubMed:19181672, ECO:0000269|PubMed:23169582}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Uruguay faciocardiomusculoskeletal syndrome (FCMSU) [MIM:300280]: A X-linked recessive syndrome characterized by brachyturricephaly, pugilistic coarse facies, a muffled voice, cardiomyopathy, muscular hypertrophy, broad hands, wide feet with progressive pes cavus deformities, dislocation of toes, variable congenital hip dislocation, and scoliosis. {ECO:0000269|PubMed:26933038}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Jak-STAT signaling pathway - Homo sapiens (human);Notch Signaling Pathway;Notch (Consensus)

Recessive Scores

• pRec: 0.136

Intolerance Scores

• rvis_EVS: -0.03
• rvis_percentile_EVS: 51.4

Haploinsufficiency Scores

• pHI: 0.459
• hipred: Y
• hipred_score: 0.762
• ghis: 0.541

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.961

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fhl1
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); homeostasis/metabolism phenotype; growth/size/body region phenotype; muscle phenotype

Zebrafish Information Network

• Gene name: fhl1a
• Affected structure: skeletal muscle
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: regulation of membrane depolarization;muscle organ development;animal organ morphogenesis;negative regulation of G2/M transition of mitotic cell cycle;cell differentiation;negative regulation of cell growth;positive regulation of potassium ion transport;regulation of potassium ion transmembrane transporter activity;negative regulation of G1/S transition of mitotic cell cycle
• Cellular component: nucleus;cytoplasm;cytosol;plasma membrane;focal adhesion
• Molecular function: molecular_function;protein binding;ion channel binding;metal ion binding