Submissions for variant NM_153026.3(PRICKLE1):c.2269G>A (p.Glu757Lys)

gnomAD frequency: 0.00037  dbSNP: rs145860632

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188731	SCV000242355	uncertain significance	not provided	2017-06-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the PRICKLE1 gene. The E757K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E757K variant is observed in 14/10,404 (0.1%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E757K 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. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000536124	SCV000646881	uncertain significance	Epilepsy, progressive myoclonic, 1B	2022-09-07	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 757 of the PRICKLE1 protein (p.Glu757Lys). This variant is present in population databases (rs145860632, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PRICKLE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 206655). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV002314747	SCV000847453	uncertain significance	Inborn genetic diseases	2017-12-15	criteria provided, single submitter	clinical testing	The p.E757K variant (also known as c.2269G>A), located in coding exon 7 of the PRICKLE1 gene, results from a G to A substitution at nucleotide position 2269. The glutamic acid at codon 757 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000536124	SCV000896309	uncertain significance	Epilepsy, progressive myoclonic, 1B	2018-10-31	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000536124	SCV000898904	uncertain significance	Epilepsy, progressive myoclonic, 1B	2021-03-30	criteria provided, single submitter	clinical testing	PRICKLE1 NM_153026 exon 8 p.Glu757Lys (c.2269G>A): This variant has not been reported in the literature but is present in 0.1% (29/24020) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs145860632). This variant is present in ClinVar (Variation ID:206655). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
New York Genome Center	RCV000536124	SCV002097716	uncertain significance	Epilepsy, progressive myoclonic, 1B	2020-12-29	criteria provided, single submitter	clinical testing