Submissions for variant NM_022437.3(ABCG8):c.712G>A (p.Glu238Lys)

gnomAD frequency: 0.00100  dbSNP: rs34754243

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000318546	SCV000345982	uncertain significance	not provided	2018-07-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094726	SCV000430514	uncertain significance	Sitosterolemia 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
SIB Swiss Institute of Bioinformatics	RCV000262892	SCV000803631	uncertain significance	Sitosterolemia	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Sitosterolemia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.
Invitae	RCV000318546	SCV001418294	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 238 of the ABCG8 protein (p.Glu238Lys). This variant is present in population databases (rs34754243, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia or dyslipidemia (PMID: 32041611, 32088153). ClinVar contains an entry for this variant (Variation ID: 291264). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000318546	SCV001715697	uncertain significance	not provided	2019-04-21	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000318546	SCV002011379	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365329	SCV002665776	uncertain significance	Cardiovascular phenotype	2022-11-30	criteria provided, single submitter	clinical testing	The p.E238K variant (also known as c.712G>A), located in coding exon 6 of the ABCG8 gene, results from a G to A substitution at nucleotide position 712. The glutamic acid at codon 238 is replaced by lysine, an amino acid with similar properties. This variant has been detected in hypercholesterolemia cohorts; however, additional details were limited (Reeskamp LF et al. J Clin Lipidol Jan;14:207-217.e7; Dron JS et al. BMC Med Genomics. 2020 Feb;13(1):23; Fath F et al. Sci Rep. 2021 Oct;11(1):20421). This amino acid position is well 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.
Fulgent Genetics, Fulgent Genetics	RCV002494900	SCV002800907	uncertain significance	Gallbladder disease 4; Sitosterolemia 1	2021-10-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001094726	SCV003822408	uncertain significance	Sitosterolemia 1	2023-05-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000318546	SCV003923985	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	Identified in patients with familial hypercholesterolemia in published literature, although additional clinical information and segregation information were not provided (Dron et al., 2020; Reeskamp et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32088153, 32041611)
PreventionGenetics, part of Exact Sciences	RCV003949962	SCV004761874	likely benign	ABCG8-related disorder	2022-03-23	criteria provided, single submitter	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).