NM_003978.5(PSTPIP1):c.748G>A (p.Glu250Lys) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Feb 3, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000215780.14

Allele description [Variation Report for NM_003978.5(PSTPIP1):c.748G>A (p.Glu250Lys)]

NM_003978.5(PSTPIP1):c.748G>A (p.Glu250Lys)

Gene:

PSTPIP1:proline-serine-threonine phosphatase interacting protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q24.3

Genomic location:

Preferred name:

NM_003978.5(PSTPIP1):c.748G>A (p.Glu250Lys)

HGVS:

NC_000015.10:g.77032304G>A
NG_007526.1:g.42181G>A
NM_001321135.2:c.748G>A
NM_001321136.2:c.721G>A
NM_001321137.1:c.943G>A
NM_001411086.1:c.748G>A
NM_003978.5:c.748G>AMANE SELECT
NP_001308064.1:p.Glu250Lys
NP_001308065.1:p.Glu241Lys
NP_001308066.1:p.Glu315Lys
NP_001398015.1:p.Glu250Lys
NP_003969.2:p.Glu250Lys
NP_003969.2:p.Glu250Lys
LRG_172t1:c.748G>A
LRG_172:g.42181G>A
LRG_172p1:p.Glu250Lys
NC_000015.9:g.77324645G>A
NM_001321137.1:c.943G>A
NM_003978.2:c.748G>A
NM_003978.3:c.748G>A
NM_003978.4:c.748G>A
O43586:p.Glu250Lys

Protein change:

E241K; GLU250LYS

Links:

UniProtKB: O43586#VAR_070635; OMIM: 606347.0003; dbSNP: rs28939089

NCBI 1000 Genomes Browser:

rs28939089

Molecular consequence:

NM_001321135.2:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001321136.2:c.721G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001321137.1:c.943G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001411086.1:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003978.5:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000279154	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 3, 2022)	germline	clinical testing	Citation Link,
SCV001930831	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001954840	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001965501	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002103265	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 24, 2021)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 22161697, 22513199, 25845478, 26025129, 28628471, 28960754, 29150835, 30198636, 31119601, 31789267, 32054657, 32441320, 33597285, 34399798, 34620178, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne).

Demidowich AP, Freeman AF, Kuhns DB, Aksentijevich I, Gallin JI, Turner ML, Kastner DL, Holland SM.

Arthritis Rheum. 2012 Jun;64(6):2022-7. doi: 10.1002/art.34332. Epub 2011 Dec 12.

PubMed [citation]

PMID:: 22161697
PMCID:: PMC3737487

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, Park SH, Kim SK, Choe JY, Park JS.

Clin Exp Rheumatol. 2012 May-Jun;30(3):452. Epub 2012 Jun 26. No abstract available.

PubMed [citation]

PMID:: 22513199

See all PubMed Citations (16)

Details of each submission

From GeneDx, SCV000279154.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001930831.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001954840.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001965501.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV002103265.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

PM2_supporting, PS2, PS4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 31, 2025

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