ABCG5 and ABCG8 variants associated to sitosterolemia in ClinVar – state of art

Miranda, Beatriz Raposo; Alves, Ana Catarina; Bourbon, Mafalda

http://hdl.handle.net/10400.18/8923

Use this identifier to reference this record.

Name:	Description:	Size:	Format:
Poster_Curating the clinical genome 2023_BRM.pdf		352.55 KB	Adobe PDF	Download

Send Feedback

Authors

Miranda, Beatriz Raposo

Alves, Ana Catarina

Bourbon, Mafalda

Abstract(s)

Sitosterolemia is a rare lipid disorder characterized by the accumulation of plant sterols in the blood, which can lead to several cardiovascular complications. This autosomal recessive disorder is due to pathogenic alterations in ABCG5 and ABCG8 genes. We aimed to assess ClinVar information regarding ABCG5/8 variants possibly causing sitosterolemia. ClinVar was consulted, and all variants submitted as related to “sitosterolemia” were considered (even if some of these were also associated with other phenotypes such as “cardiovascular phenotype”). ClinVar review status of two stars (multiple submissions, no conflicts), one star (single submissions or conflicting interpretations) and no stars (no assertion criteria provided) were considered. The file extracted for ABCG5 analysis contained 295 variants and the file extracted for ABCG8 contained 138 variants. In both files appeared variants mentioning both genes ABCG5/ABCG8 (=11). These were not considered for the descriptive analysis to avoid overcounting. Concerning ABCG5 variants (n=295), 24 are classified as pathogenic/likely pathogenic (3 with review status of two stars, 7 with one, and 6 with no stars); 67 as benign/likely benign (25 with two stars and 42 with one star). Additionally, 160 were classified as variants of uncertain significance (VUS) (61 with two stars, 98 with one, and 1 with no stars), and 44 have conflicting interpretations of pathogenicity (review status of one star). In the ABCG8 variants file (n=138), 16 are classified as pathogenic/likely pathogenic (7 with review status of two stars, 5 with one star, and 4 with no stars); and 26 as benign/likely benign (all with two stars). Additionally, 59 were found classified as VUS (28 with two stars and 31 with one star), and 37 have conflicting interpretations of pathogenicity (review status of one star). Despite there is information in ClinVar about these variants being found in homozygosity/compound heterozygosity in sitosterolemia patients (enabling a genotype-phenotype analysis), the great majority of variants in both genes lack other kind of information as functional characterization and in silico prediction analysis. ClinVar constitutes a fundamental tool for data sharing and to be consulted to know if a specific variant has been reported elsewhere but lacks other important information for variant classification. Although the majority are nonsense variants there are still many missense variants that need other type of information to be classified as pathogenic and this poses an important gap in sitosterolemia diagnosis. It remains crucial to improve the classification and knowledge of ABCG5/8 variants since the correct genetic diagnosis of sitosterolemia is vital for a personalized treatment.