ClinVar Miner

Submissions for variant NM_153026.3(PRICKLE1):c.132G>A (p.Gln44=) (rs377668062)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188735 SCV000242359 uncertain significance not provided 2014-06-06 criteria provided, single submitter clinical testing p.Gln44Gln (CAG>CAA): c.132 G>A in exon 2 of the PRICKLE1 gene (NM_153026.2). The c.132 G>A variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The c.132 G>A 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. Multiple in silico algorithms predict that c.132 G>A may damage or destroy the natural donor splice site in intron 2; however, in the absence of RNA/functional studies, the actual effect of c.132 G>A on splicing is unknown. Additionally, to our knowledge, no splice site mutations have been described in the PRICKLE1 gene. 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 CHILD-EPI panel(s).
Invitae RCV000646037 SCV000767793 uncertain significance Progressive myoclonus epilepsy with ataxia 2018-09-07 criteria provided, single submitter clinical testing This sequence change affects codon 44 of the PRICKLE1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PRICKLE1 protein. This variant also falls at the last nucleotide of exon 2 of the PRICKLE1 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs377668062, ExAC 0.02%). This variant has not been reported in the literature in individuals with PRICKLE1-related disease. ClinVar contains an entry for this variant (Variation ID: 206659). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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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