Submissions for variant NM_022436.3(ABCG5):c.593G>A (p.Arg198Gln)

gnomAD frequency: 0.00109  dbSNP: rs141828689

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000658134	SCV000337331	uncertain significance	not provided	2018-06-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000286622	SCV000593005	uncertain significance	not specified	2017-06-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000658134	SCV000779905	uncertain significance	not provided	2018-05-24	criteria provided, single submitter	clinical testing	The R198Q variant in the ABCG5 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R198Q variant is observed in 276/126,586 (0.2%) alleles from individuals of non-Finnish European background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). The R198Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R198Q as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000986627	SCV001035770	likely benign	Sitosterolemia	2024-01-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000986627	SCV001135670	uncertain significance	Sitosterolemia	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000658134	SCV001152242	uncertain significance	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001141655	SCV001302016	uncertain significance	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Revvity Omics, Revvity	RCV003137889	SCV003822389	uncertain significance	Sitosterolemia 2	2023-09-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298337	SCV003999274	uncertain significance	Cardiovascular phenotype	2023-05-25	criteria provided, single submitter	clinical testing	The p.R198Q variant (also known as c.593G>A), located in coding exon 5 of the ABCG5 gene, results from a G to A substitution at nucleotide position 593. The arginine at codon 198 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported as heterozygous in familial hypercholesterolemia cohorts (Lamiquiz-Moneo I et al. J Clin Lipidol, 2017 Oct;11:1432-1440.e4; Pillai KKB et al. Clin Chim Acta, 2022 Feb;527:47-55; Rutkowska L et al. Genes (Basel), 2022 Jun;13:[ePub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV000658134	SCV004224879	uncertain significance	not provided	2023-02-24	criteria provided, single submitter	clinical testing	PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000286622	SCV005380836	uncertain significance	not specified	2024-08-08	criteria provided, single submitter	clinical testing	Variant summary: ABCG5 c.593G>A (p.Arg198Gln) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251200 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCG5 causing Early Onset Coronary Artery Disease (0.0012 vs 0.005), allowing no conclusion about variant significance. c.593G>A has been reported in the literature in individuals affected with Hypercholesterolemias and Sitosterolemia (Lamiquiz-Moneo_2017, Dron_2020, Dong_2022,Toton-Zuranska_2023), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. 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: 35460704, 32041611, 29066094, 36648309). ClinVar contains an entry for this variant (Variation ID: 284636). Based on the evidence outlined above, the variant was classified as uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000658134	SCV001963432	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000658134	SCV001979090	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752822	SCV005345559	likely benign	ABCG5-related disorder	2024-09-19	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).