ClinGen Dosage Sensitivity Curation Page

GPC3

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
30447178 Vuillaume et al. (2018) reviewed 57 previously described GPC3 variants identified in 71 unrelated families. In addition they identified and additional 38 GPC3 variants in tn a patient cohort of 49 unrelated families. Variant types included large deletions (34.9%) followed by frameshift mutations leading to a stop premature codon (24.4%), nonsense (16.3%), missense (8.1%), large intragenic duplications (8.1%), splice site mutations (4.7%), translocations (2.3%), and one in frame mutation (1.2%).
21362501 Weichert et al. (2011) reported the prenatal findings of a fetus with a 1 MB deletion that includes the entire GPC3 gene, arr Xq26.2(132191191_133257323)x0; NCBI Build 36.1) and encompassing GPC4, GPC3 and CCDC160 . The most commonly found antenatal features of postnatally confirmed cases of SGBS1 included craniofacial anomalies, marked macrosomia, increased nuchal translucency and polyhydramnios.
10814714 Veuglelers et al. (2000) identified 6 SBGS1 patients with variants predicted to result in loss of function (1 frameshift, 3 nonsense, 1 splice site, 1 intragenic deletion . Expression analysis studies of one missense variant W296R that changes a highly conserved amnio acid resulted in a poorly processed protein and failed to increase the cell surface expression of heparan sulfate, suggesting that this missense mutation is also a loss-of-function mutation.

Haploinsufficiency phenotype comments:

Pathogenic variants resulting loss of function including splice site, frameshift, nonsense variants, intragenic deletions, intragenic duplications and whole gene deletions of the GPC3 gene have been found in males with Simpson-Golabi-Behmel syndrome type 1 (SGBS1). Clinical features of SGBS1 include pre- and post-natal overgrowth, developmental delay, macrocephaly, and distinct facial features. Additional features which may be seen include congenital heart defects, kidney anomalies and skeletal anomalies and an increased risk of embryonal cancers. Additional PMIDs include 6538755, 8589713,9192268. Females are typically asymptomatic although some females have been noted with various features. Skewed X-inactivation has been a suggested explanation for clinical expression in some females. Additional PMIDs include 2739211and 30048822.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.