FUCA1

protein-coding

alpha-L-fucosidase 1, the group of Alpha-L-fucosidases

Gene summary

The protein encoded by this gene is a lysosomal enzyme involved in the degradation of fucose-containing glycoproteins and glycolipids. Mutations in this gene are associated with fucosidosis (FUCA1D), which is an autosomal recessive lysosomal storage disease. A pseudogene of this locus is present on chr 2.[provided by RefSeq, Oct 2009]

MANE transcript

NM_000147.5

Inheritance

ClinVar variants

P:93U:148B:147

Top phenotype

Fucosidosis

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr1:23,845,077-23,868,290

External References & Databases

Ensembl (ENSG00000179163)

Transcript & Mutation Effects

hg38 • Region Span ~23.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

fucosidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009254

Submitter: Labcorp Genetics (formerly Invitae)

fucosidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009254

Submitter: G2P

fucosidosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009254

Submitter: Orphanet

fucosidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009254

Submitter: Genomics England PanelApp

fucosidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009254

Submitter: ClinGen

The relationship between the FUCA1 gene and fucosidosis, an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 27, 2022. FUCA1 encodes alpha-L-fucosidase, a lysosomal enzyme involved in the degradation of fucose-containing glycoproteins and glycolipids via cleaving via hydrolyzing alpha-fucose moieties at the non-reducing terminus of oligosaccharides (PMID: 2803312). Among patients with fucosidosis, alpha-fucosidase deficiency results in the accumulation of fucose-containing glycoproteins and glycolipids in multiple tissues (PMID: 4172303, PMID: 4241464). The disease mechanism of fucosidosis is loss of function. Fucosidosis was first reported in 1968 by Van Hoof and Hers (PMID: 4172303) and the first report of biallelic variants in FUCA1 among patients with fucosidosis in 1989 by Kretz (PMID: 2642067). Both case-level (genetic) and experimental evidence support the relationship between FUCA1 and fucosidosis. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 33266441, PMID: 2642067, PMID: 1281988, PMID: 8097260, PMID: 8401503, PMID: 8401503, PMID: 9039984, PMID: 8081399). In total, eight variants from seven probands in six publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between FUCA1 and fucosidosis includes: the biochemical function of the gene product (alpha-fucosidase) being consistent with the clinical and biochemical findings identified individuals with fucosidosis (PMID: 4172303, PMID: 4241464); the biochemical and clinical features of FUCA1 knockout mice (PMID: 27491075); and rescue of alpha-fucosidase enzyme function via hematopoietic cell transplantation in a patient with fucosidosis (PMID: 11360116). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, FUCA1 is definitively associated with fucosidosis. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on August 2, 2022 (SOP v9).

fucosidosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009254

Submitter: PanelApp Australia

fucosidosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009254

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

FucosidosisAR

Manifestation: Biochemical; Dermatologic; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 4172303; 4241464; 4247654; 5026163; 1214294; 4128078; 7460371; 6538300; 2903667; 3409541; 2642067; 2012122; 8719750; 9039984; 9762612; 10094192; 12408193; 17427030; 18504684

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FUCA1 variants in ClinVar

8 Conditions Cataloged

FucosidosisTotal: 403

Inborn genetic diseasesTotal: 67

not providedTotal: 61

not specifiedTotal: 24

FUCA1-related disorderTotal: 17

FUCA1-related disordersTotal: 3

Intellectual disabilityTotal: 3

Abnormality of the nervous systemTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000147.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	125 clinvar	1 clinvar	127
missense	3 clinvar	8 clinvar	141 clinvar	20 clinvar	1 clinvar	173
nonsense	24 clinvar	14 clinvar	2 clinvar			40
start loss			1 clinvar			1
frameshift	19 clinvar	11 clinvar	1 clinvar			31
splice donor/acceptor (+/-2bp)	4 clinvar	10 clinvar	2 clinvar			16
Total	50	43	148	145	2	388

Highest pathogenic variant AF is 0.000022304694

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000147.5	RefSeq	NP_000138.2	8	MANE Select
ENST00000374479.4	Ensembl	ENSP00000363603.3	8	MANE Select
ENST00000881205.1	Ensembl	ENSP00000551264.1	7	Standard
ENST00000881205.2	Ensembl	ENSP00000551264.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Other glycan degradation - Homo sapiens (human)
Neutrophil degranulation
Post-translational protein modification
Reactions specific to the complex N-glycan synthesis pathway

Biological Process

fucose metabolic process
glycosaminoglycan catabolic process
glycoside catabolic process
glycolipid catabolic process
neutrophil degranulation

Molecular Function

alpha-L-fucosidase activity

Cellular Component

extracellular region
cytoplasm
lysosome
azurophil granule lumen
lysosomal lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374479
Coding exons: 8
Length: 23218
Individuals with no LoFs: 125717
Homozygous LoFs: 0
Heterozygous LoFs: 31
Defined: 125748
p: 0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.845	218	256	0.851	0.0000129	3003
Missense (PolyPhen)		83	97.872	0.84804		1199
Synonymous	0.206	98	101	0.974	0.00000514	896
Loss of Function	1.78	16	25.7	0.621	0.00000120	261

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Alpha-L-fucosidase is responsible for hydrolyzing the alpha-1,6-linked fucose joined to the reducing-end N- acetylglucosamine of the carbohydrate moieties of glycoproteins.;
Disease: DISEASE: Fucosidosis (FUCA1D) [MIM:230000]: An autosomal recessive lysosomal storage disease characterized by accumulation of fucose- containing glycolipids and glycoproteins in various tissues. Clinical signs include facial dysmorphism, dysostosis multiplex, moderate hepatomegaly, severe intellectual deficit, deafness, and according to age, angiokeratomas. {ECO:0000269|PubMed:7874128, ECO:0000269|PubMed:8504303, ECO:0000269|PubMed:9762612}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.293

Intolerance Scores

LoFtool: 0.869
RVIS EVS: 0.66
RVIS percentile EVS: 84.55

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.861

Gene Damage Prediction

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