Submissions for variant NM_153026.3(PRICKLE1):c.1547G>C (p.Trp516Ser) (rs139901494)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000717833	SCV000848693	uncertain significance	Seizures	2017-01-08	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence
GeneDx	RCV000188747	SCV000242371	uncertain significance	not provided	2018-05-23	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the PRICKLE1 gene. The W516S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The W516S variant 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 W516S 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. Additionally, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000467028	SCV000551464	uncertain significance	Progressive myoclonus epilepsy with ataxia	2018-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan with serine at codon 516 of the PRICKLE1 protein (p.Trp516Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. This variant is present in population databases (rs139901494, ExAC 0.01%). This variant has not been reported in the literature in individuals with PRICKLE1-related disease. ClinVar contains an entry for this variant (Variation ID: 206670). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.