ClinVar Miner

Submissions for variant NM_153026.3(PRICKLE1):c.25A>G (p.Met9Val) (rs566073131)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188733 SCV000242357 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing p.Met9Val (ATG>GTG): c.25 A>G in exon 2 of the PRICKLE1 gene (NM_153026.2). The c.25 A>G variant 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, indicating it is not a common benign variant in these populations. Multiple in silico algorithms predict c.25 A>G may create a cryptic splice donor site upstream of the natural donor site. However, in the absence of RNA/functional studies, the actual effect of the c.25 A>G on splicing is unknown. If c.25 A>G does not alter splicing, it will result in the M9V missense change which is a conservative amino acid substitution that is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000646044 SCV000767801 uncertain significance Progressive myoclonus epilepsy with ataxia 2017-12-05 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 9 of the PRICKLE1 protein (p.Met9Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs566073131, ExAC 0.05%). This variant has not been reported in the literature in individuals with PRICKLE1-related disease. ClinVar contains an entry for this variant (Variation ID: 206657). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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