ClinVar Miner

Submissions for variant NM_153026.3(PRICKLE1):c.100G>A (p.Ala34Thr)

gnomAD frequency: 0.00001  dbSNP: rs781255236
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478636 SCV000565770 uncertain significance not provided 2017-02-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PRICKLE1 gene. The A34T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A34T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A34T 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. This substitution occurs at a position that is conserved in mammals; however, Threonine is observed at this position in evolution. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001865431 SCV002288399 uncertain significance Epilepsy, progressive myoclonic, 1B 2021-08-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 34 of the PRICKLE1 protein (p.Ala34Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs781255236, ExAC 0.01%). This missense change has been observed in individual(s) with clinical features of PRICKLE1-related conditions (PMID: 29358611). ClinVar contains an entry for this variant (Variation ID: 418596). 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.
Bioinformatics Core, Luxembourg Center for Systems Biomedicine RCV000656032 SCV000588308 pathogenic Self-limited epilepsy with centrotemporal spikes 2017-01-01 no assertion criteria provided case-control CAADphred>15

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