ClinVar

Description

Variant summary: ABCG8 c.1285A>G (p.Met429Val) results in a conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 251444 control chromosomes, predominantly at a frequency of 0.004 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.05-fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCG8 causing Sitosterolemia phenotype (0.0038), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1285A>G has been reported in the literature in East Asian individuals affected with Sitosterolemia or familial hypercholesterolemia without strong evidence of causality (e.g. Pek_2018, Miwa_2005, Tada_2018, Tada_2018b, Tada_2022, Kojima_2020, Nomura_2020). These reports do not provide unequivocal conclusions about association of the variant with Sitosterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29353225, 15816807, 30241732, 32275988, 32862661, 32088153, 35248527, 30007774). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=1), benign (n=1) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.