Submissions for variant NM_022437.3(ABCG8):c.1752G>A (p.Trp584Ter)

dbSNP: rs754182905

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272852	SCV002557260	pathogenic	Sitosterolemia 1	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with sitosterolemia 1 (MIM#210250). (I) 0106 - This gene is associated with autosomal recessive disease. However, at least one family has been reported with a heterozygous ABCG8 variant that appeared to segregate in an autosomal dominant manner with hypercholesterolaemia (PMID: 31327807). However, this association is not well established and other sources conclude that heterozygous variants in this gene may only be a partial and multifactorial contributor to hypercholesterolaemia (PMIDs: 35549507, 32088153). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, PMID: 35549507). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV005058207	SCV005720851	pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp584*) in the ABCG8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCG8 are known to be pathogenic (PMID: 11452359, 15375183, 16029460). This variant is present in population databases (rs754182905, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ABCG8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1698995). For these reasons, this variant has been classified as Pathogenic.