Submissions for variant NM_003978.5(PSTPIP1):c.688G>A (p.Ala230Thr)

dbSNP: rs121908130

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000419297	SCV000514293	pathogenic	not provided	2023-10-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate increased pyrin binding and hyperphosphorrylation as well as increased IL-1b secretion (Wang et al., 2013; Samukawa et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16738958, 21438098, 24421327, 25040622, 26025129, 23426477, 17213252, 21790734, 25845478, 22878270, 35152348, 20506269, 34880353, 34262554, 34620178, 19934105, 34745107, 33218716, 28696038, 33338535, 34492165, 29148036, 34435004, 28236224, 35840971, 31471736, 28421071, 19673875, 15580218, 22513199, 28243699, 31139187, 11971877, 21325428, 22161697, 30467586, 34938582, 14595024, 17964261, 19584923, 23293022)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004685	SCV000820801	pathogenic	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome	2023-08-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PSTPIP1 function (PMID: 11971877, 14595024, 19934105, 20506269). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PSTPIP1 protein function. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 230 of the PSTPIP1 protein (p.Ala230Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) (PMID: 11971877, 15580218, 19673875, 22161697, 22513199, 26025129). It has also been observed to segregate with disease in related individuals. This variant is also known as c.904G>A. ClinVar contains an entry for this variant (Variation ID: 4435).
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000004685	SCV001468468	pathogenic	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome	2021-03-30	criteria provided, single submitter	clinical testing	PSTPIP1 NM_003978.4 exon 10 .pAla230Thr (c.688G>A): This variant has been reported in the literature in at least 5 individuals with Pyogenic Arthritis, Pyoderma gangrenosum and Acne syndrome (PAPA), segregating with disease in 10 affected family members (Wise 2002 PMID:11971877, Cortesio 2010 PMID:20506269, Demidowich 2012 PMID:22161697, Schaffler 2019 PMID:30467586). This variant is not present in large control databases. This variant is present in ClinVar, with two labs classifying this variant as pathogenic (Variation ID:4435). Evolutionary conservation for this variant is unclear; computational predictive tools suggest that this variant may not impact the protein. In vitro and in vivo (mouse) functional studies support that this variant will impact the protein, suggesting impaired binding to PTP-PEST (Wise 2002 PMID:11971877, Cortesio 2010 PMID:20506269, Wang 2013 PMID:23293022). In summary, this variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000419297	SCV001501086	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000004685	SCV004030486	pathogenic	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415651	SCV004108050	pathogenic	PSTPIP1-related disorder	2022-12-18	criteria provided, single submitter	clinical testing	The PSTPIP1 c.688G>A variant is predicted to result in the amino acid substitution p.Ala230Thr. In the literature, this variant is also referred to as 904G>A or G904A. This variant has been reported in individuals with pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome (Wise et al. 2002. PubMed ID: 11971877; Cortesio et al. 2010. PubMed ID: 20506269; Demidowich et al. 2011. PubMed ID: 22161697). Of note, this variant was shown to segregate with disease in affected families (Wise et al. 2002. PubMed ID: 11971877). Yeast two-hybrid assays showed that this variant lead to severely reduced binding ability of the protein (Wise et al. 2002. PubMed ID: 11971877). Additional function studies showed that this variant lead to defects in mononuclear cell podosome formation and migration of macrophages (Cortesio et al. 2010. PubMed ID: 20506269). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is interpreted as pathogenic in ClinVar by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/4435/). This variant is interpreted as pathogenic.
OMIM	RCV000004685	SCV000024860	pathogenic	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome	2002-04-15	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000419297	SCV001926676	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000419297	SCV001955557	pathogenic	not provided		no assertion criteria provided	clinical testing