Submissions for variant NM_022437.3(ABCG8):c.1285A>G (p.Met429Val)

dbSNP: rs147194762

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000596406	SCV000705663	uncertain significance	not provided	2017-02-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001137121	SCV001297025	benign	Sitosterolemia 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000596406	SCV001657461	likely benign	not provided	2024-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000596406	SCV002504438	likely benign	not provided	2019-10-08	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330815	SCV004039551	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV001137121	SCV004238907	uncertain significance	Sitosterolemia 1	2023-09-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952976	SCV004782456	likely benign	ABCG8-related disorder	2023-10-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).