GPC3

Chr XXLR

glypican 3

Also known as: DGSX, GTR2-2, MXR7, OCI-5, SDYS, SGB, SGBS, SGBS1

NCBI Gene: 2719 ENSG00000147257 UniProt: P51654

Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

Primary Disease Associations & Inheritance

Simpson-Golabi-Behmel syndrome, type 1MIM #312870

XLR

Wilms tumor, somaticMIM #194070

526

ClinVar variants

111

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— GPC3

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Gene-Disease Validity (ClinGen)

Simpson-Golabi-Behmel syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

111 Pathogenic / Likely Pathogenic· 252 VUS of 526 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

LoF intolerant — likely haploinsufficient

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.

0.16LOEUF

pLI 0.998

Z-score 3.98

OE 0.00 (0.00–0.16)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.

1.45Z-score

OE missense 0.73 (0.64–0.83)

161 obs / 221.9 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.0.00 (0.00–0.16)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.64–0.83)

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.0.99

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	0	83	0	96
Likely Pathogenic	7	1	7	0	15
VUS	2	229	19	2	252
Likely Benign	1	24	37	55	117
Benign	0	5	2	11	18
Conflicting	—				28
Total	23	259	148	68	526

GPC3

Primary Disease Associations & Inheritance

Population Genetics & Constraint

ClinVar Variant Classifications

Classification Summary

Curated Variants Distribution

Protein Context — Lollipop Plot

DECIPHER · Gene2Phenotype

Gene2Phenotype Curations

OMIM — Genotype-Phenotype Relationships

Gene Overview

ClinGen Curation

Disease Associations

External Resources

Variant Interpretation

Population Databases

Gene Resources