NM_003978.5(PSTPIP1):c.657A>G (p.Gln219=) AND Pyogenic arthritis-pyoderma gangrenosum-acne syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Feb 21, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_003978.5(PSTPIP1):c.657A>G (p.Gln219=)]

NM_003978.5(PSTPIP1):c.657A>G (p.Gln219=)

PSTPIP1:proline-serine-threonine phosphatase interacting protein 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_003978.5(PSTPIP1):c.657A>G (p.Gln219=)
  • NC_000015.10:g.77031194A>G
  • NG_007526.1:g.41071A>G
  • NM_001321135.2:c.657A>G
  • NM_001321136.2:c.630A>G
  • NM_001321137.1:c.852A>G
  • NM_003978.5:c.657A>GMANE SELECT
  • NP_001308064.1:p.Gln219=
  • NP_001308065.1:p.Gln210=
  • NP_001308066.1:p.Gln284=
  • NP_003969.2:p.Gln219=
  • LRG_172t1:c.657A>G
  • LRG_172:g.41071A>G
  • NC_000015.9:g.77323535A>G
  • NM_003978.3:c.657A>G
  • NR_135552.2:n.1025A>G
dbSNP: rs139362350
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NR_135552.2:n.1025A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_001321135.2:c.657A>G - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001321136.2:c.630A>G - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_001321137.1:c.852A>G - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_003978.5:c.657A>G - synonymous variant - [Sequence Ontology: SO:0001819]


Pyogenic arthritis-pyoderma gangrenosum-acne syndrome
Pyogenic arthritis, pyoderma gangrenosum and acne; Pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne; Familial recurrent arthritis
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)
SCV000943277Invitaecriteria provided, single submitter
Uncertain significance
(Feb 21, 2020)
germlineclinical testing

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

SCV001278162Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely benign
(Jan 12, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

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



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]

Details of each submission

From Invitae, SCV000943277.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)


This sequence change affects codon 219 of the PSTPIP1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PSTPIP1 protein. This variant is present in population databases (rs139362350, ExAC 0.008%). This variant has not been reported in the literature in individuals with PSTPIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 507898). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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

From Illumina Clinical Services Laboratory,Illumina, SCV001278162.1

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


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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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

Last Updated: Oct 7, 2021

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