NM_001039569.2(AP1S3):c.97C>T (p.Arg33Trp) AND Psoriasis 15, pustular, susceptibility to

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Apr 20, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000148042.6

Allele description [Variation Report for NM_001039569.2(AP1S3):c.97C>T (p.Arg33Trp)]

NM_001039569.2(AP1S3):c.97C>T (p.Arg33Trp)

Gene:

AP1S3:adaptor related protein complex 1 subunit sigma 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q36.1

Genomic location:

Preferred name:

NM_001039569.2(AP1S3):c.97C>T (p.Arg33Trp)

HGVS:

NC_000002.12:g.223777776G>A
NG_034017.1:g.64827C>T
NM_001039569.2:c.97C>TMANE SELECT
NP_001034658.1:p.Arg33Trp
NC_000002.11:g.224642493G>A
NM_001039569.1:c.97C>T
NR_110905.2:n.229C>T
NR_110906.2:n.229C>T
Q96PC3:p.Arg33Trp

Protein change:

R33W; ARG33TRP

Links:

UniProtKB: Q96PC3#VAR_072549; OMIM: 615781.0001; dbSNP: rs138292988

NCBI 1000 Genomes Browser:

rs138292988

Molecular consequence:

NM_001039569.2:c.97C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_110905.2:n.229C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110906.2:n.229C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Psoriasis 15, pustular, susceptibility to (PSORS15)
Identifiers:: MONDO: MONDO:0014494; MedGen: C4015235; Orphanet: 247353; OMIM: 616106

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000195548	OMIM	no assertion criteria provided	risk factor (May 1, 2014)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 24791904, 28887889
SCV002796576	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 20, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000195548

OMIM

no assertion criteria provided

risk factor
(May 1, 2014)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV002796576

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Apr 20, 2022)

unknown

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking.

Setta-Kaffetzi N, Simpson MA, Navarini AA, Patel VM, Lu HC, Allen MH, Duckworth M, Bachelez H, Burden AD, Choon SE, Griffiths CE, Kirby B, Kolios A, Seyger MM, Prins C, Smahi A, Trembath RC, Fraternali F, Smith CH, Barker JN, Capon F.

Am J Hum Genet. 2014 May 1;94(5):790-7. doi: 10.1016/j.ajhg.2014.04.005.

PubMed [citation]

PMID:: 24791904
PMCID:: PMC4067562

The genetic basis for most patients with pustular skin disease remains elusive.

Mössner R, Wilsmann-Theis D, Oji V, Gkogkolou P, Löhr S, Schulz P, Körber A, Prinz JC, Renner R, Schäkel K, Vogelsang L, Peters KP, Philipp S, Reich K, Ständer H, Jacobi A, Weyergraf A, Kingo K, Kõks S, Gerdes S, Steinz K, Schill T, et al.

Br J Dermatol. 2018 Mar;178(3):740-748. doi: 10.1111/bjd.15867. Epub 2018 Jan 22.

PubMed [citation]

PMID:: 28887889

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000195548.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 9 patients with pustular psoriasis (PSORS15; 616106), including 1 with the generalized form, 4 with the palmoplantar form, and 4 with the acral form, Setta-Kaffetzi et al. (2014) identified heterozygosity for a c.97C-T transition in the AP1S3 gene, resulting in an arg33-to-trp (R33W) substitution at the AP1M1A (see 603535) interface. AP1S3-knockdown HaCaT cells overexpressing R33W protein showed reduced TLR3 (603029) processing. The c.97T-C allele frequency was significantly higher in affected individuals (3.6%) than in 1,695 unrelated controls (0.7%; p = 2.3 x 10(-5)). Segregation analysis in a representative pedigree revealed that the proband had inherited the c.97C-T disease allele from an unaffected parent. Setta-Kaffetzi et al. (2014) suggested that the lack of family history among patients with AP1S3 mutations reflects the requirement of environmental triggers, such as infection, pregnancy, or drug exposure, for disease development.

In 3 patients with palmoplantar pustular psoriasis, 1 with acute generalized exanthematous pustulosis, and 1 with generalized pustular psoriasis (GPP), Mossner et al. (2018) identified heterozygosity for the R33W mutation in the AP1S3 gene. The patient with GPP was also homozygous for a missense mutation in the IL36RN gene (S113L; 605507.0001).

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

From Fulgent Genetics, Fulgent Genetics, SCV002796576.1

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

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

Last Updated: Jun 17, 2024

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