Submissions for variant NM_005506.4(SCARB2):c.277G>A (p.Glu93Lys)

gnomAD frequency: 0.00016  dbSNP: rs145870223

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188812	SCV000242436	uncertain significance	not specified	2016-09-29	criteria provided, single submitter	clinical testing	A variant of unknown significance has been identified in the SCARB2 gene. The E93K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The E93K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense pathogenic variants in nearby residues have not been reported in the Human Gene Mutation Database in association (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000462122	SCV000545818	uncertain significance	Progressive myoclonic epilepsy	2022-10-13	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 93 of the SCARB2 protein (p.Glu93Lys). This variant is present in population databases (rs145870223, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with focal epilepsy and sudden unexpected death in epilepsy (SUDEP) (PMID: 29261713). ClinVar contains an entry for this variant (Variation ID: 206724). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Athena Diagnostics Inc	RCV000188812	SCV000615018	uncertain significance	not specified	2017-03-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000734839	SCV000863013	uncertain significance	not provided	2018-08-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433852	SCV002747260	uncertain significance	Inborn genetic diseases	2019-05-15	criteria provided, single submitter	clinical testing	The p.E93K variant (also known as c.277G>A), located in coding exon 3 of the SCARB2 gene, results from a G to A substitution at nucleotide position 277. The glutamic acid at codon 93 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in an epilepsy cohort (Coll M et al. PLoS ONE, 2017 Dec;12:e0189618). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485281	SCV002780819	uncertain significance	Action myoclonus-renal failure syndrome	2022-04-16	criteria provided, single submitter	clinical testing