Submissions for variant NM_022437.3(ABCG8):c.788G>A (p.Arg263Gln)

gnomAD frequency: 0.00006  dbSNP: rs137852990

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727975	SCV000855491	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000727975	SCV002273612	pathogenic	not provided	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 263 of the ABCG8 protein (p.Arg263Gln). This variant is present in population databases (rs137852990, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of sitosterolemia (PMID: 11452359, 24166850, 24657386, 29886606; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4970). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ABCG8 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000005258	SCV003822395	uncertain significance	Sitosterolemia 1	2021-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004984635	SCV005473279	likely pathogenic	Cardiovascular phenotype	2024-11-14	criteria provided, single submitter	clinical testing	The p.R263Q variant (also known as c.788G>A), located in coding exon 6 of the ABCG8 gene, results from a G to A substitution at nucleotide position 788. The arginine at codon 263 is replaced by glutamine, an amino acid with highly similar properties. This variant has been identified in the homozygous state and/or in conjunction with other ABCG8 variant(s) in individual(s) with features consistent with sitosterolemia; in at least one instance, the variants were identified in trans (Hansel B et al. Atherosclerosis, 2014 May;234:162-8; Wang Z et al. Am J Hematol, 2014 Mar;89:320-4; Helgadottir A et al. Eur Heart J, 2020 Jul;41:2618-2628; Fermo E et al. Front Physiol, 2021 May;12:684569; Xia Y et al. J Clin Lipidol, 2022 Dec;16:40-51). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
OMIM	RCV000005258	SCV000025436	pathogenic	Sitosterolemia 1	2000-12-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003407279	SCV004113205	likely pathogenic	ABCG8-related disorder	2024-03-08	no assertion criteria provided	clinical testing	The ABCG8 c.788G>A variant is predicted to result in the amino acid substitution p.Arg263Gln. This variant has been reported in the compound heterozygous state with a truncating ABCG8 variant in an individual with sitosterolemia (Wang et al. 2014. PubMed ID: 24166850). This variant has also been reported in individuals with sitosterolemia (phytosterolemia) or familial hypercholesterolemia (Berge et al. 2000. PubMed ID: 11099417; Hansel et al. 2014. PubMed ID: 24657386; Reeskamp et al. 2020. PubMed ID: 32088153). This variant is reported in 0.13% of alleles in individuals of East Asian descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic.