GeneBe

GLA

protein-coding

galactosidase alpha, the group of Galactosidases alpha

Gene summary

This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000169.3

Inheritance

XL

ClinVar variants

P:1171U:422B:175

Top phenotype

Fabry disease; Fabry disease, cardiac variant

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:101,393,273-101,408,012

External References & Databases

Ensembl (ENSG00000102393)NCBI Gene (2717)OMIM (300644)HGNC:4296GenCCUniProt (P06280)AlphaFoldClinVar (GLA)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~14.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fabry diseaseDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010526

Submitter: Natera

Fabry diseaseSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010526

Submitter: Labcorp Genetics (formerly Invitae)

Fabry diseaseDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010526

Submitter: G2P

Fabry diseaseSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010526

Submitter: Genomics England PanelApp

Fabry diseaseSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010526

Submitter: Orphanet

Fabry diseaseDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010526

Submitter: ClinGen

The relationship between GLA and Fabry disease, an X-linked lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of March 3rd, 2017. Deficiency of the gene product, alpha-galactosidase A, was first reported in males with Fabry disease in 1967 (Brady et al; PMID 6023233), and variants in GLA were first associated with this disease in 1989 (Bernstein et al, PMID 2539398). Over 400 unique variants, including missense, nonsense, splice site, frameshift, in-frame deletions, and complex rearrangements, have been reported in humans (reviewed in Gal et al, 2006, PMID 21290673; Mehta, 2017, PMID 20301469). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Twenty-five variants were curated in 25 probands from 3 publications (Bernstein et al, 1989, PMID 2539398; Topaloglu et al, 1989, PMID 10666480; Shimotori et al, 2008, PMID 18205205). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is loss of function. This gene-disease association is supported by the function of the gene product (Brady et al, 1967, PMID 6020428) animal models and rescue (Oshima et al, 1997, PMID 9122231; Taguchi et al, 2013, PMID 24094090), and studies of the clinical impact of enzyme replacement therapy in humans (Beck et al, 2015, PMID 26937390). In summary, GLA is definitively associated with Fabry disease. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Fabry disease; Fabry disease, cardiac variantXL

Manifestation: Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Dermatologic; Neurologic; Ophthalmologic; Renal

Intervention: Biochemical; Cardiovascular; Renal

Rationale: In individuals with Fabry disease, enzyme therapy is available; Both males and females with variants can suffer from significant multisystemic disease manifestations (including cardiovascular, cerebrovascular, and renal disease) and require monitoring and treatment, which can reduce morbidity; Individuals with Cardiac variant Fabry disease can have adult-onset left ventricular hypertrophy with or without renal failure, and early diagnosis and medical management may be beneficial

Refs: 5411915; 4914726; 5466114; 6294821; 6283080; 3107860; 2539398; 2120125; 1645238; 1846223; 8395937; 7879606; 7817917; 7596372; 8807334; 8738659; 11105184; 10618424; 11694547; 11179018; 11732485; 11530143; 11386930; 11804208; 11889412; 12911529; 12519371; 15253767; 15162124; 15154115; 16298216; 16533976; 16926253; 16980809; 17371887; 17256799; 17362993; 17224688; 18023222; 19473999; 19318041; 19843486; 19853240; 19959221; 19965549; 19745746; 20301469; 21502868; 22431073; 22450713; 22498845; 22704481; 22731890; 22878429; 22880956; 22881192; 22880956; 22898981; 22963910; 22998007; 23040658; 23089251; 23094092; 23703683; 31860127Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GLA variants in ClinVar

19 Conditions Cataloged
Fabry diseaseTotal: 1845
not providedTotal: 418
Cardiovascular phenotypeTotal: 187
not specifiedTotal: 84
Migalastat responseTotal: 46
GLA-related disorderTotal: 35
CardiomyopathyTotal: 21
Fabry disease, cardiac variantTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000169.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
11
clinvar
152
clinvar
2
clinvar
 166
missense
233
clinvar
459
clinvar
397
clinvar
21
clinvar
 1110
nonsense
110
clinvar
13
clinvar
4
clinvar
 127
start loss
4
clinvar
2
clinvar
 6
frameshift
246
clinvar
51
clinvar
3
clinvar
 300
splice donor/acceptor (+/-2bp)
43
clinvar
9
clinvar
7
clinvar
 59
Total63753442217321768

Highest pathogenic variant AF is 0.00003486664

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000169.3RefSeqNP_000160.17MANE Select
ENST00000218516.4EnsemblENSP00000218516.47MANE Select
NM_001406747.1RefSeqNP_001393676.18Standard
NM_001406748.1RefSeqNP_001393677.16Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Glycerolipid metabolism - Homo sapiens (human)
  • Lysosome - Homo sapiens (human)
  • Glycosphingolipid biosynthesis - globo and isoglobo series - Homo sapiens (human)
  • Sphingolipid metabolism - Homo sapiens (human)
  • Galactose metabolism - Homo sapiens (human)

Biological Process

  • glycosphingolipid metabolic process
  • oligosaccharide metabolic process
  • glycoside catabolic process
  • neutrophil degranulation
  • negative regulation of nitric oxide biosynthetic process

Molecular Function

  • catalytic activity
  • alpha-galactosidase activity
  • signaling receptor binding
  • protein binding
  • hydrolase activity

Cellular Component

  • extracellular region
  • cytoplasm
  • lysosome
  • Golgi apparatus
  • azurophil granule lumen

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000218516
Coding exons
7
Length
10123
Individuals with no LoFs
125704
Homozygous LoFs
0
Heterozygous LoFs
1
Defined
125705
p
0.00000398
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.88931600.5820.00001112846
Missense (PolyPhen)2367.5110.340691238
Synonymous0.5595055.30.9040.00000373794
Loss of Function3.80016.90.000.00000135227

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000120.0000088rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease
DISEASE: Fabry disease (FD) [MIM:301500]: Rare X-linked sphingolipidosis disease where glycolipid accumulates in many tissues. The disease consists of an inborn error of glycosphingolipid catabolism. FD patients show systemic accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes throughout the body. Clinical recognition in males results from characteristic skin lesions (angiokeratomas) over the lower trunk. Patients may show ocular deposits, febrile episodes, and burning pain in the extremities. Death results from renal failure, cardiac or cerebral complications of hypertension or other vascular disease. Heterozygous females may exhibit the disorder in an attenuated form, they are more likely to show corneal opacities. {ECO:0000269|PubMed:10090526, ECO:0000269|PubMed:10208848, ECO:0000269|PubMed:10666480, ECO:0000269|PubMed:10838196, ECO:0000269|PubMed:10916280, ECO:0000269|PubMed:11076046, ECO:0000269|PubMed:11295840, ECO:0000269|PubMed:11668641, ECO:0000269|PubMed:11889412, ECO:0000269|PubMed:12694230, ECO:0000269|PubMed:12786754, ECO:0000269|PubMed:1315715, ECO:0000269|PubMed:15162124, ECO:0000269|PubMed:15712228, ECO:0000269|PubMed:16533976, ECO:0000269|PubMed:1846223, ECO:0000269|PubMed:19621417, ECO:0000269|PubMed:2152885, ECO:0000269|PubMed:2171331, ECO:0000269|PubMed:2539398, ECO:0000269|PubMed:26415523, ECO:0000269|PubMed:27142856, ECO:0000269|PubMed:27211852, ECO:0000269|PubMed:7504405, ECO:0000269|PubMed:7531540, ECO:0000269|PubMed:7575533, ECO:0000269|PubMed:7596372, ECO:0000269|PubMed:7599642, ECO:0000269|PubMed:7759078, ECO:0000269|PubMed:8069316, ECO:0000269|PubMed:8395937, ECO:0000269|PubMed:8738659, ECO:0000269|PubMed:8807334, ECO:0000269|PubMed:8834244, ECO:0000269|PubMed:8863162, ECO:0000269|PubMed:8875188, ECO:0000269|PubMed:8931708, ECO:0000269|PubMed:9100224, ECO:0000269|PubMed:9105656, ECO:0000269|PubMed:9452068, ECO:0000269|PubMed:9452090, ECO:0000269|PubMed:9452111, ECO:0000269|PubMed:9554750}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.742

Intolerance Scores

RVIS EVS
0.04
RVIS percentile EVS
56.92

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.981

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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