GBA1

Chr 1ADMultiAR

glucosylceramidase beta 1

Also known as: GBA, GCB, GLUC

NCBI Gene: 2629 ENSG00000177628 UniProt: P04062

This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]

Primary Disease Associations & Inheritance

{Lewy body dementia, susceptibility to}MIM #127750

{Parkinson disease, late-onset, susceptibility to}MIM #168600

ADMulti

Gaucher disease, perinatal lethalMIM #608013

Gaucher disease, type IMIM #230800

Gaucher disease, type IIMIM #230900

Gaucher disease, type IIIMIM #231000

Gaucher disease, type IIICMIM #231005

UniProtGaucher disease 1

UniProtGaucher disease 2

UniProtGaucher disease 3

UniProtGaucher disease 3C

582

ClinVar variants

208

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— GBA1

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Gene-Disease Validity (ClinGen)

Parkinson disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

208 Pathogenic / Likely Pathogenic· 269 VUS of 582 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

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.

0.80LOEUF

pLI 0.000

Z-score 2.36

OE 0.51 (0.34–0.80)

Tolerant

Typical tolerance to LoF variation

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.

1.17Z-score

OE missense 0.81 (0.73–0.90)

248 obs / 305.8 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.0.51 (0.34–0.80)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.73–0.90)

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.1.05

0≤1.21.6

LoF obs/exp: 14 / 27.3Missense obs/exp: 248 / 305.8Syn Z: -0.40

ClinVar Variant Classifications

582 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic89

Likely Pathogenic119

VUS269

Likely Benign51

Benign7

Conflicting47

Pathogenic

119

Likely Pathogenic

269

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	41	30	0	89
Likely Pathogenic	23	78	18	0	119
VUS	3	201	37	28	269
Likely Benign	0	2	8	41	51
Benign	0	1	6	0	7
Conflicting	—				47
Total	44	323	99	69	582

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

View in ClinVar →

Protein Context — Lollipop Plot

GBA1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GBA1-related Gaucher disease perinatal lethal

definitive

ARLoss Of FunctionAbsent Gene Product

Dev. DisordersSkin

G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

GLUCOSIDASE, BETA, ACID; GBA

MIM #606463 · *

{Lewy body dementia, susceptibility to}

MIM #127750