Submissions for variant NM_003978.5(PSTPIP1):c.668G>A (p.Arg223Gln)

gnomAD frequency: 0.00002  dbSNP: rs777380464

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816406	SCV000956913	uncertain significance	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome	2022-11-12	criteria provided, single submitter	clinical testing	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. 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 expected to disrupt PSTPIP1 protein function. ClinVar contains an entry for this variant (Variation ID: 659405). This variant has not been reported in the literature in individuals affected with PSTPIP1-related conditions. This variant is present in population databases (rs777380464, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 223 of the PSTPIP1 protein (p.Arg223Gln).
Illumina Laboratory Services, Illumina	RCV000816406	SCV001278164	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001766717	SCV001990142	uncertain significance	not provided	2019-05-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002264012	SCV002542893	uncertain significance	Autoinflammatory syndrome	2017-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004028887	SCV005012949	uncertain significance	Inborn genetic diseases	2024-01-09	criteria provided, single submitter	clinical testing	The c.668G>A (p.R223Q) alteration is located in exon 10 (coding exon 10) of the PSTPIP1 gene. This alteration results from a G to A substitution at nucleotide position 668, causing the arginine (R) at amino acid position 223 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.