ClinVar Miner

Submissions for variant NM_003978.5(PSTPIP1):c.748G>A (p.Glu250Lys) (rs28939089)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000215780 SCV000279154 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing The E250K variant in the PSTPIP1 gene has been reported previously in individuals with PAPA syndrome (Lindwall et al., 2015; Lee et al., 2012; Demidowich et al., 2012), and in individuals with hyperzincaemia and hypercalprotectinaemia (Holzinger et al., 2011). The E250K variant is not observed in large population cohorts (Lek et al., 2016). The E250K 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. Functional studies demonstrate altered function for E250K, with significantly increased binding to pyrin and an increase in phosphorylation by cABL, when compared to wild type (Holzinger et al., 2015). We interpret E250K as a pathogenic variant
Invitae RCV000084063 SCV000826795 pathogenic Pyogenic arthritis-pyoderma gangrenosum-acne syndrome 2020-01-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 250 of the PSTPIP1 protein (p.Glu250Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with PAPA syndrome or hyperzincemia and hypercalprotectinemia (PMID: 22513199, 25845478, 22161697, 26025129). ClinVar contains an entry for this variant (Variation ID: 97810). 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. A different missense substitution at this codon (p.Glu250Gln) has been determined to be pathogenic (PMID: 16527883, 20506269, 22161697, 11971877). This suggests that the glutamic acid residue is critical for PSTPIP1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000084063 SCV001369246 pathogenic Pyogenic arthritis-pyoderma gangrenosum-acne syndrome 2019-07-09 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM5,PP3.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000084063 SCV000116186 not provided Pyogenic arthritis-pyoderma gangrenosum-acne syndrome no assertion provided not provided

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