ClinVar Miner

Submissions for variant NM_153026.3(PRICKLE1):c.2269G>A (p.Glu757Lys) (rs145860632)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188731 SCV000242355 uncertain significance not provided 2017-06-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PRICKLE1 gene. The E757K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E757K variant is observed in 14/10,404 (0.1%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E757K 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. However, this substitution occurs at a position that is not conserved. 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.
Invitae RCV000536124 SCV000646881 uncertain significance Progressive myoclonus epilepsy with ataxia 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 757 of the PRICKLE1 protein (p.Glu757Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs145860632, ExAC 0.1%). This variant has not been reported in the literature in individuals with PRICKLE1-related disease. ClinVar contains an entry for this variant (Variation ID: 206655). 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.
Ambry Genetics RCV000716611 SCV000847453 uncertain significance Seizures 2017-12-15 criteria provided, single submitter clinical testing Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000536124 SCV000896309 uncertain significance Progressive myoclonus epilepsy with ataxia 2018-10-31 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000536124 SCV000898904 uncertain significance Progressive myoclonus epilepsy with ataxia 2017-12-06 criteria provided, single submitter clinical testing PRICKLE1 NM_153026.2 exon 8 p.Glu757Lys (c.2269G>A): This variant has not been reported in the literature but is present in 0.1% (29/24020) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs145860632). This variant is present in ClinVar (Variation ID:206655). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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