ABCG5

Inheritance Pattern: AR

Disease ID:MONDO:0020748

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0008863

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0020748

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0008863

Submitter: ClinGen

The relationship between ABCG5 and sitosterolemia, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of January, 2019. ABCG5 was reported in relation to sitosterolemia as early as 2001 (Berge et al, PMID: 11099417; Lee et al, 2001, PMID: 11138003). At least 12 unique variants including nonsense, splice site, frameshift and missense variants have been reported in humans. ABCG5 encodes an ATP-binding cassette half-transporter and functions to limit intestinal absorption and promote biliary excretion of sterols. Sitosterolemia is characterized by increased intestinal absorption and decreased biliary excretion of plant sterols, leading to extremely high plasma levels of plant sterols. Patients with the disorder can develop tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease (PMID: 11099417). The hematological presentation of sitosterolemia has been previously described as Mediterranean stomatocytosis/macrothrombocytopenia. Stomatocytic hemolysis, large platelets, splenomegaly and abnormal bleeding can be associated features in about 30% of cases (PMID: 32546081); however, hematologic manifestations can sometimes be the only clinical sign of sitosterolemia (PMID: 16029460). While the mechanisms underlying the hematological features shown by some sitosterolemia patients remains unknown, it is proposed that the accumulation of circulating plant sterols into blood cell membranes results in their altered morphology and dysfunction (PMID: 32546081). Variants in both genes, ABCG5 and ABCG8, which share 28% homology, have been reported in relation to sitosterolemia (PMID: 11099417). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 11 probands in 5 publications (PMID: 11138003, 28203044, 17976197, 16029460, 28521186). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is biallelic loss of function (PMID: 11099417) Summary of Experimental Data: 6 Points This gene-disease association is supported by mouse model evidence and in vitro functional assays. ABCG5 is strongly expressed in the liver and small intestine (PMID: 11099417). ABCG5 functions similar to and interacts with ABCG8 to form a heterodimer for transportation to the cell surface (PMID: 12208867, 14504269, 19846887). ABCG5 knockout in mice recapitulates the sitosterolemia phenotype, including macrothrombocytopenia and affected mice were rescued by expression of the wild-type protein (PMID: 14699507, 19846887). In summary, ABCG5 is definitively associated with Autosomal Recessive Sitosterolemia. 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 Hemostasis/Thrombosis GCEP on July 10, 2020 (SOP Version 6).

Inheritance Pattern: AR

Disease ID:MONDO:0020747

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AR

Disease ID:MONDO:0020747

Submitter: Labcorp Genetics (formerly Invitae)