ClinVar Miner

Submissions for variant NM_153026.3(PRICKLE1):c.2216C>T (p.Ser739Phe) (rs138452760)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000712847 SCV000843386 uncertain significance not provided 2017-09-14 criteria provided, single submitter clinical testing
Bioinformatics Core,Luxembourg Center for Systems Biomedicine RCV000656030 SCV000588306 pathogenic Rolandic epilepsy 2017-01-01 no assertion criteria provided case-control CAADphred>15
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000712847 SCV000232794 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing
GeneDx RCV000712847 SCV000242380 uncertain significance not provided 2018-08-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PRICKLE1 gene. The S739F variant in the PRICKLE1 gene was previously identified in a patient with myelomeningocele and was not detected in controls so it was suggested to contribute to an increased risk for open neural tube defects; however, the variant was inherited from the patient's unaffected mother and did not co-segregate with neural tube defects in the extended family (Bosoi et al., 2011). The S739F variant is observed in 181/126496 (0.14%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. However, the S739F 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000525823 SCV000646880 uncertain significance Progressive myoclonus epilepsy with ataxia 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 739 of the PRICKLE1 protein (p.Ser739Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs138452760, ExAC 0.1%). This variant has been reported in an individual affected with myelomeningocele, however this variant was also present in the unaffected mother and did not segregate with neural tube defects in the family (PMID: 21901791). ClinVar contains an entry for this variant (Variation ID: 198918). 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 disruptive, 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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