NM_003978.5(PSTPIP1):c.1213C>T (p.Arg405Cys) AND Pyogenic arthritis-pyoderma gangrenosum-acne syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Benign(1);Likely benign(1);Uncertain significance(1) (Last evaluated: Nov 18, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000286501.8

Allele description [Variation Report for NM_003978.5(PSTPIP1):c.1213C>T (p.Arg405Cys)]

NM_003978.5(PSTPIP1):c.1213C>T (p.Arg405Cys)

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.1213C>T (p.Arg405Cys)
HGVS:
  • NC_000015.10:g.77037138C>T
  • NG_007526.1:g.47015C>T
  • NM_001321135.2:c.1156C>T
  • NM_001321136.2:c.1186C>T
  • NM_001321137.1:c.1408C>T
  • NM_003978.5:c.1213C>TMANE SELECT
  • NP_001308064.1:p.Arg386Cys
  • NP_001308065.1:p.Arg396Cys
  • NP_001308066.1:p.Arg470Cys
  • NP_003969.2:p.Arg405Cys
  • LRG_172t1:c.1213C>T
  • LRG_172:g.47015C>T
  • NC_000015.9:g.77329479C>T
  • NM_003978.3:c.1213C>T
  • NR_135552.2:n.1393C>T
Protein change:
R386C
Links:
dbSNP: rs201253322
NCBI 1000 Genomes Browser:
rs201253322
Molecular consequence:
  • NM_001321135.2:c.1156C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001321136.2:c.1186C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001321137.1:c.1408C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003978.5:c.1213C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_135552.2:n.1393C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Pyogenic arthritis-pyoderma gangrenosum-acne syndrome
Synonyms:
Pyogenic arthritis, pyoderma gangrenosum and acne; Pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne; Familial recurrent arthritis
Identifiers:
MONDO: MONDO:0011462; MedGen: C1858361; Orphanet: 69126; OMIM: 604416

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000394021Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Benign
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV000642079Invitaecriteria provided, single submitter
Likely benign
(Nov 18, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001159699ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(Jul 31, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000394021.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000642079.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001159699.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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