ClinVar Miner

Submissions for variant NM_003978.5(PSTPIP1):c.1213C>T (p.Arg405Cys) (rs201253322)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000229743 SCV000291956 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing To our knowledge, the R405C missense substitution in the PSTPIP1 gene has neither been published as a pathogenic variant, nor as a benign polymorphism. This variant was not observed in any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. R405C represents a non-conservative amino acid substitution as a positively-charged Arginine residue is replaced with a neutral Cysteine residue. The position in the PSTPIP1 protein where this substitution occurs is moderately conserved among species and is part of a binding domain of the protein. In addition, the gain of a Cysteine residue could affect the structure of the protein by affecting disulfide bond formation. However, this substitution does not occur in the coiled-coil domain region, the region where definitive PAPA-associated variants have been identified to date. Therefore, based on the currently available information, it is unclear whether R405C is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,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.
Invitae RCV000286501 SCV000642079 likely benign Pyogenic arthritis-pyoderma gangrenosum-acne syndrome 2020-11-18 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.