ClinVar Genomic variation as it relates to human health
NM_003978.5(PSTPIP1):c.748G>A (p.Glu250Lys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003978.5(PSTPIP1):c.748G>A (p.Glu250Lys)
Variation ID: 97810 Accession: VCV000097810.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q24.3 15: 77032304 (GRCh38) [ NCBI UCSC ] 15: 77324645 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 20, 2014 Feb 14, 2024 Dec 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003978.5:c.748G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003969.2:p.Glu250Lys missense NM_001321135.2:c.748G>A NP_001308064.1:p.Glu250Lys missense NM_001321136.2:c.721G>A NP_001308065.1:p.Glu241Lys missense NM_001321137.1:c.943G>A NP_001308066.1:p.Glu315Lys missense NC_000015.10:g.77032304G>A NC_000015.9:g.77324645G>A NG_007526.1:g.42181G>A LRG_172:g.42181G>A LRG_172t1:c.748G>A O43586:p.Glu250Lys - Protein change
- E250K, E241K, E315K
- Other names
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- Canonical SPDI
- NC_000015.10:77032303:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PSTPIP1 | - | - |
GRCh38 GRCh37 |
654 | 679 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2023 | RCV000084063.16 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 3, 2022 | RCV000215780.14 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Pyogenic arthritis-pyoderma gangrenosum-acne syndrome
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369246.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM5,PP3.
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Pathogenic
(Nov 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002103265.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
PM2_supporting, PS2, PS4
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Pathogenic
(Aug 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Pyogenic arthritis-pyoderma gangrenosum-acne syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768649.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
A heterozygous missense variant, NM_003978.3(PSTPIP1):c.748G>A, has been identified in exon 11 of 15 of the PSTPIP1 gene. The variant is predicted to result in a … (more)
A heterozygous missense variant, NM_003978.3(PSTPIP1):c.748G>A, has been identified in exon 11 of 15 of the PSTPIP1 gene. The variant is predicted to result in a amino acid change from glutamic acid to lysine at position 250 of the protein (NP_003969.2(PSTPIP1):p.(Glu250Lys)). The glutamic acid at this position has conservation (100 vertebrates, UCSC), and is located within the BAR superfamily domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously reported pathogenic in multiple patients with hypercalprotectinemia and hyperzincemia (Hz/Hc) (Holzinger, D. et al., 2015). It has also been shown de novo in at least 8 patients and inherited in one family (Holzinger, D. et al., 2015). Additionally, studies demonstrated it impacts protein function (Holzinger, D. et al., 2015). A different variant in the same codon resulting in a change to glutamine is known to cause the classic phenotype, PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) (Holzinger, D. et al., 2015). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
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Pathogenic
(Feb 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000279154.10
First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate altered function for E250K, with significantly increased binding to pyrin and an increase in phosphorylation by cABL, when compared to wild … (more)
Published functional studies demonstrate altered function for E250K, with significantly increased binding to pyrin and an increase in phosphorylation by cABL, when compared to wild type (Holzinger et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22161697, 28628471, 29150835, 26989109, 25845478, 26025129, 28832562, 31119601, 32441320, 28960754, 33256319, 32054657, 29453417, 33597285, 22513199) (less)
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Pathogenic
(Mar 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pyogenic arthritis-pyoderma gangrenosum-acne syndrome
Affected status: yes
Allele origin:
de novo
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Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust
Accession: SCV003853408.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Pyogenic arthritis-pyoderma gangrenosum-acne syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002505389.2
First in ClinVar: Apr 30, 2022 Last updated: Feb 04, 2024 |
Sex: male
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Pathogenic
(Dec 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pyogenic arthritis-pyoderma gangrenosum-acne syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000826795.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 250 of the PSTPIP1 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 250 of the PSTPIP1 protein (p.Glu250Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PAPA syndrome or hyperzincemia and hypercalprotectinemia (PMID: 22161697, 22513199, 25845478, 26025129). ClinVar contains an entry for this variant (Variation ID: 97810). 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 with a positive predictive value of 80%. This variant disrupts the p.Glu250 amino acid residue in PSTPIP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11971877, 16527883, 20506269, 22161697). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930831.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954840.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965501.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Pyogenic arthritis-pyoderma gangrenosum-acne syndrome
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927938.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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not provided
(-)
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no classification provided
Method: not provided
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Pyogenic arthritis, pyoderma gangrenosum and acne
Affected status: not provided
Allele origin:
not provided
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Unité médicale des maladies autoinflammatoires, CHRU Montpellier
Accession: SCV000116186.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical and genetic characteristics of PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome. | Zhang D | Pediatric rheumatology online journal | 2021 | DOI: 10.1186/s12969-021-00636-9 |
Clinical and genetic characteristics of PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome. | Zhang D | Pediatric rheumatology online journal | 2021 | PMID: 34620178 |
Immunological repertoire linked to PSTPIP1-associated myeloid-related inflammatory (PAMI) syndrome. | Mendonça LO | Pediatric rheumatology online journal | 2021 | PMID: 34399798 |
Hemolysis and Neurologic Impairment in PAMI Syndrome: Novel Characteristics of an Elusive Disease. | Del Borrello G | Pediatrics | 2021 | PMID: 33597285 |
Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes. | Blombery P | Haematologica | 2021 | PMID: 32054657 |
Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity. | Suspitsin EN | Clinical genetics | 2020 | PMID: 32441320 |
Extensive pyoderma gangrenosum-like lesions revealing a case of hyperzincemia and hypercalprotectinemia: when to suspect it? | Resende LO | Anais brasileiros de dermatologia | 2019 | PMID: 31789267 |
Autoinflammation Masquerading as Autoimmunity in an Adult with Heterozygous p.E250K PSTPIP1 Mutation. | Dai P | Journal of clinical immunology | 2019 | PMID: 31119601 |
PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome: A rare cause of childhood neutropenia associated with systemic inflammation and hyperzincemia. | Hashmi SK | Pediatric blood & cancer | 2019 | PMID: 30198636 |
The expanding spectrum of clinical phenotypes associated with PSTPIP1 mutations: from PAPA to PAMI syndrome and beyond. | Klötgen HW | The British journal of dermatology | 2018 | PMID: 29150835 |
Genetic heterogeneity of uncharacterized childhood autoimmune diseases with lymphoproliferation. | Takagi M | Pediatric blood & cancer | 2018 | PMID: 28960754 |
Haematological involvement associated with a mild autoinflammatory phenotype, in two patients carrying the E250K mutation of PSTPIP1. | Belelli E | Clinical and experimental rheumatology | 2017 | PMID: 28628471 |
Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. | Holzinger D | The Journal of allergy and clinical immunology | 2015 | PMID: 26025129 |
Novel PSTPIP1 gene mutation in a patient with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome. | Lindwall E | Seminars in arthritis and rheumatism | 2015 | PMID: 25845478 |
Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome) with E250K mutation in CD2BP1 gene treated with the tumor necrosis factor inhibitor adalimumab. | Lee H | Clinical and experimental rheumatology | 2012 | PMID: 22513199 |
Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne). | Demidowich AP | Arthritis and rheumatism | 2012 | PMID: 22161697 |
Impaired podosome formation and invasive migration of macrophages from patients with a PSTPIP1 mutation and PAPA syndrome. | Cortesio CL | Arthritis and rheumatism | 2010 | PMID: 20506269 |
Peculiarities of PAPA syndrome. | Tallon B | Rheumatology (Oxford, England) | 2006 | PMID: 16527883 |
Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. | Wise CA | Human molecular genetics | 2002 | PMID: 11971877 |
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Text-mined citations for rs28939089 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.