Submission Details

GPC3 was first reported in relation to X-linked Simpson-Golabi-Behmel syndrome in 1996 (Pilia et al., PMID: 8589713). Simpson-Golabi-Behmel syndrome is characterized by pre- and postnatal overgrowth, coarse facies, congenital heart defects, mild to severe intellectual disability with or without structural brain anomalies, and other congenital abnormalities. While normal intelligence has been reported, 47% of the Simpson-Golabi-Behmel patients with GPC3 variants have intellectual disability (Cottereau et al., PMID: 23606591). Carrier females may have mild manifestations due to skewed X-inactivation.

More than 27 unique pathogenic variants in GPC3 have been reported in ClinVar. An overview of 86 distinct GPC3 variants documented in a study showed that the vast majority of them are deletions or truncating mutations (Vuillaume et al., PMID: 29637653). 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 (Vuillaume et al., PMID: 29637653). This gene-disease relationship is also supported by animal models. It is noteworthy that Simpson-Golabi-Behmel syndrome can also be caused by variants in OFD1 (see OMIM).

In summary, there is definitive evidence supporting the relationship between GPC3 and X-linked Simpson-Golabi-Behmel syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 31, 2019 (SOP Version 6).

GPC3 was reported in relation to X-linked Simpson-Golabi-Behmel syndrome in 1996 (Pilia, et al., PMID: 8589713). Simpson-Golabi-Behmel syndrome is characterized by pre- and postnatal overgrowth, coarse facies, congenital heart defects, mild to severe intellectual disability with or without structural brain anomalies, and other congenital abnormalities. While normal intelligence has been reported, 47% of the Simpson-Golabi-Behmel patients with GPC3 variants have intellectual disability (Cottereau, et al., PMID: 23606591). Carrier females may have mild manifestations due to skewed X-inactivation. More than 27 unique pathogenic variants in GPC3 have been reported in ClinVar. An overview of 86 distinct GPC3 variants documented in a study showed that the vast majority of them are deletions or truncating mutations (Vuillaume, et al., PMID: 29637653). Evidence supporting this gene-disease relationship includes case-level data and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is loss-of-function in GPC3 (Vuillaume, et al., PMID: 29637653). The gene-disease association is also supported by animal models. Noteworthy, Simpson-Golabi-Behmel syndrome can be caused by variants in OFD1 as well (see OMIM). In summary, GPC3 is definitively associated with X-linked Simpson-Golabi-Behmel syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 12/30/19 (SOP Version 7).