Gene Validity Curation

GPC3 - Simpson-Golabi-Behmel syndrome

Gene: GPC3 (HGNC:4451)
Classification - 12/31/2019
Disease: Simpson-Golabi-Behmel syndrome (MONDO_0010731)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism EP
Evidence Summary: 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).
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 2
4
4
Vuillaume ML et al. 2018 Jun (PMID:29637653);
Proband with predicted or proven null variant 1.5 0-2 10 8 13 10
Vuillaume ML et al. 2018 Jun (PMID:29637653); Veugelers M et al. 2000 May 22 (PMID:10814714);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 1.5 1.5
Cano-Gauci DF et al. 1999 Jul 12 (PMID:10402475); Chiao E et al. 2002 Mar 1 (PMID:11846487);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 1.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 1.5 13.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
12/31/2019
EXPERT CURATION (DATE)
Definitive
12/31/2019
EVIDENCE SUMMARY
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).