ClinVar Miner

Submissions for variant NM_153026.3(PRICKLE1):c.2105G>A (p.Arg702Gln) (rs369790443)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724229 SCV000232798 uncertain significance not provided 2014-12-02 criteria provided, single submitter clinical testing
GeneDx RCV000188749 SCV000242373 uncertain significance not specified 2013-04-09 criteria provided, single submitter clinical testing p.Arg702Gln (CGG>CAG): c.2105 G>A in exon 8 of the PRICKLE1 gene (NM_153026.2). The Arg702Gln missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or among the various ethnic groups studied in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative as a positively charged Arginine residue is replaced by an uncharged Glutamine residue. Arg702Gln alters a position, that is conserved in mammals, in the Vangl/Dgo binding domain of the protein. However, other missense mutations have not been reported in this region of the protein in association with epilepsy and in-silico algorithms are not consistent in their predictions of whether Arg702Gln is damaging to the structure/function of hte protein. Therefore, based on the currently available information, it is unclear whether Arg702Gln is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000796891 SCV000936424 uncertain significance Progressive myoclonus epilepsy with ataxia 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 702 of the PRICKLE1 protein (p.Arg702Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs369790443, ExAC 0.03%). This variant has not been reported in the literature in individuals with PRICKLE1-related disease. ClinVar contains an entry for this variant (Variation ID: 198920). 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, 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.

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