Submissions for variant NM_003978.5(PSTPIP1):c.1213C>T (p.Arg405Cys)

gnomAD frequency: 0.00049  dbSNP: rs201253322

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000229743	SCV000291956	uncertain significance	not provided	2022-02-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R405C may alter the interaction of PSTPIP1 with cytoskeleton and cell migration regulators (Starnes et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This substitution does not occur in the coiled-coil domain region, the region where definitive PAPA-associated variants have been identified to date.; This variant is associated with the following publications: (PMID: 24764557, 27106250, 26713508, 30619323, 24421327, 32909274, 34764798, 32942279)
Illumina Laboratory Services, Illumina	RCV000286501	SCV000394021	benign	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000286501	SCV000642079	likely benign	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome	2024-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000286501	SCV001159699	uncertain significance	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome	2018-07-31	criteria provided, single submitter	clinical testing	The PSTPIP1 c.1213C>T; p.Arg405Cys variant (rs201253322) is reported in the literature in at least one individual affected with pyoderma gangrenosum, acne and suppurative hidradenitis (PASH) syndrome (Calderon-Castrat 2016), and in multiple individuals affected with pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome (Starnes 2014). This variant is reported as uncertain significance by several laboratories in ClinVar (Variation ID: 242307), and is found in the general population with an overall allele frequency of 0.057% (155/277726 alleles) in the Genome Aggregation Database. The arginine at codon 405 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, functional analyses of the variant protein show increased WASP activity resulting in membrane degradation in macrophages (Starnes 2014). Due to conflicting information, the clinical significance of the c.1213C>T; p.Arg405Cys variant is uncertain at this time. References: Calderon-Castrat X et al. PSTPIP1 gene mutation in a pyoderma gangrenosum, acne and suppurative hidradenitis (PASH) syndrome. Br J Dermatol. 2016 Jul;175(1):194-8. Starnes TW et al. The F-BAR protein PSTPIP1 controls extracellular matrix degradation and filopodia formation in macrophages. Blood. 2014 Apr 24;123(17):2703-14.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262847	SCV002542855	uncertain significance	Autoinflammatory syndrome	2022-04-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003955381	SCV004786103	likely benign	PSTPIP1-related disorder	2023-11-03	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).