Submissions for variant NM_003978.5(PSTPIP1):c.1208G>A (p.Gly403Glu)

gnomAD frequency: 0.00026  dbSNP: rs201572812

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000225897	SCV000291955	uncertain significance	not specified	2016-01-28	criteria provided, single submitter	clinical testing	The G403E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G403E 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. This substitution occurs at a position within the SH3 region that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same codon (G403R) has been reported in the Human Gene Mutation Database in association with pyoderma gangrenosum, acne, and ulcerative colitis (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the pathogenicity of missense changes in the SH3 region of the PSTPIP1 protein is unclear, as pathogenic variants associated with PAPA syndrome have traditionally been identified in the coiled-coil domain region. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Laboratory Services, Illumina	RCV000394861	SCV000394020	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	RCV000394861	SCV000642078	uncertain significance	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 403 of the PSTPIP1 protein (p.Gly403Glu). This variant is present in population databases (rs201572812, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hidradenitis suppurativa (PMID: 37013170). ClinVar contains an entry for this variant (Variation ID: 242306). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PSTPIP1 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PSTPIP1 function (PMID: 37013170). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000394861	SCV001472773	uncertain significance	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome	2023-10-26	criteria provided, single submitter	clinical testing	The PSTPIP1 c.1208G>A; p.Gly403Glu variant (rs201572812), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 242306). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (52/126858 alleles) in the Genome Aggregation Database. The glycine at codon 403 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another amino acid substitution at this codon (p.Gly403Arg) has been reported in an individual with pyoderma gangrenosum, acne and ulcerative colitis, although its clinical significance in this individual was not demonstrated (Zeeli 2015). Due to limited information, the clinical significance of the p.Gly403Glu variant is uncertain at this time. References: Zeeli T et al. Pyoderma gangrenosum, acne and ulcerative colitis in a patient with a novel mutation in the PSTPIP1 gene. Clin Exp Dermatol. 2015 Jun;40(4):367-72.
Mayo Clinic Laboratories, Mayo Clinic	RCV002261020	SCV002541287	uncertain significance	not provided	2021-07-08	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262846	SCV002542854	uncertain significance	Autoinflammatory syndrome	2020-02-01	criteria provided, single submitter	clinical testing