VCV000030490.55 - ClinVar

NM_012275.3(IL36RN):c.338C>T (p.Ser113Leu)

Germline

Classification

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.

(14)

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.

Conflicting classifications of pathogenicity
Pathogenic(5); Likely pathogenic(2); Uncertain significance(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_012275.3(IL36RN):c.338C>T (p.Ser113Leu)

Variation ID: 30490 Accession: VCV000030490.55

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q14.1 2: 113062547 (GRCh38) [ NCBI UCSC ] 2: 113820124 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Nov 28, 2014	Oct 20, 2024	Jun 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_012275.3:c.338C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036407.1:p.Ser113Leu	missense
NM_173170.1:c.338C>T	NP_775262.1:p.Ser113Leu	missense
NC_000002.12:g.113062547C>T
NC_000002.11:g.113820124C>T
NG_031864.1:g.8910C>T
LRG_730:g.8910C>T
LRG_730t1:c.338C>T	LRG_730p1:p.Ser113Leu
LRG_730t2:c.338C>T	LRG_730p2:p.Ser113Leu
	Q9UBH0:p.Ser113Leu

... more HGVS ... less HGVS

Protein change

S113L

Other names

Canonical SPDI

NC_000002.12:113062546:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00160 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00156

1000 Genomes Project 0.00160

Trans-Omics for Precision Medicine (TOPMed) 0.00220

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00231

The Genome Aggregation Database (gnomAD) 0.00264

Links

ClinGen: CA129270 UniProtKB: Q9UBH0#VAR_066648 OMIM: 605507.0002 dbSNP: rs144478519 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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 Help 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.
IL36RN		-	-	GRCh38 GRCh37	190	213

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Generalized pustular psoriasis	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Mar 31, 2024	RCV000023447.22
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jun 11, 2024	RCV000513043.32
Autoinflammatory syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 5, 2022	RCV002262572.4
Acrodermatitis continua suppurativa of Hallopeau	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 11, 2022	RCV002288518.6
IL36RN-related disorder	Likely pathogenic (1)	no assertion criteria provided	Aug 27, 2024	RCV003415734.6

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 Help 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.
Pathogenic (Dec 07, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Acrodermatitis continua suppurativa of Hallopeau Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915854.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (5) PubMed: 23648549‚ 23428889‚ 23303454‚ 21839423‚ 27220475 Comment: Across a selection of the available literature, the IL36RN c.338C>T (p.Ser113Leu) missense variant has been identified in six patients in a homozygous state, in five … (more) Across a selection of the available literature, the IL36RN c.338C>T (p.Ser113Leu) missense variant has been identified in six patients in a homozygous state, in five patients in a compound heterozygous state, and in two patients in a heterozygous state. One heterozygous individual carried additional variants in the CARD14 gene (Onoufriadis et al. 2011; Setta-Kaffetzi et al. 2013; Abbas et al. 2013; Korber et al. 2013). The variant was also found in a heterozygous state in unaffected parents and was absent from 440 control individuals (Onoufriadis et al. 2011; Korber et al. 2013). This variant is reported at a frequency of 0.006635 in the European (non-Finnish) population of the Genome Aggregation Database. Two studies have evaluated the functional impact of this variant. Tauber et al. (2016) transfected the p.Ser113Leu variant form of the IL-36Ra protein into HEK293 cells and observed reduced protein expression. In addition, there was a decreased inhibitory effect on NF-kB activity compared to wild type activity. In a second study, Setta-Kaffetzi et al. (2013) used peripheral blood mononuclear cells from one patient who was homozygous for the p.Ser113Leu variant and one unrelated healthy individual and observed increased cytokine production in the presence of the variant compared to the control. Based on the collective evidence, the p.Ser113Leu variant is classified as pathogenic for generalized pustular psoriasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Apr 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autoinflammatory syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002543486.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Uncertain significance (Jan 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrodermatitis continua suppurativa of Hallopeau Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580566.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4_MOD, PM3, PS3_SUP, BS1	Number of individuals with the variant: 1 Sex: female
Uncertain significance (Oct 24, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Generalized pustular psoriasis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000756812.6 First in ClinVar: Apr 09, 2018 Last updated: Feb 07, 2023	Publications: PubMed (11) PubMed: 21839423‚ 23303454‚ 23428889‚ 23648549‚ 25427108‚ 25458002‚ 26147717‚ 27388993‚ 28887889‚ 30036598‚ 27220475 Comment: This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 113 of the IL36RN protein (p.Ser113Leu). … (more) This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 113 of the IL36RN protein (p.Ser113Leu). This variant is present in population databases (rs144478519, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau (ACH) (PMID: 21839423, 23303454, 23428889, 23648549, 25427108, 25458002, 26147717, 27388993, 28887889, 30036598). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects IL36RN function (PMID: 27220475). 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. (less)
Pathogenic (Jun 11, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005078075.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: Common variant among individuals of European background (PMID: 24656634); Published functional studies suggest this variant results in reduced protein expression and partial impairment of capacity … (more) Common variant among individuals of European background (PMID: 24656634); Published functional studies suggest this variant results in reduced protein expression and partial impairment of capacity to repress an IL36RNmediated signaling cascade, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 27220475); 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: 25468355, 24131530, 23428889, 25458002, 25212972, 23792462, 21839423, 25989471, 22288582, 23648549, 22903787, 23303454, 23711932, 26589685, 25427108, 23909475, 23834760, 27038307, 27388993, 29030861, 30609409, 34426522, 38577038, 37414245, 26147717, 24656634, 27220475) (less)
Likely pathogenic (Mar 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502202.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (10) PubMed: 21839423‚ 23428889‚ 23792462‚ 30609409‚ 27388993‚ 25989471‚ 25427108‚ 29030861‚ 23303454‚ 27220475 Number of individuals with the variant: 3 Secondary finding: no
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715715.2 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Publications: PubMed (12) PubMed: 21839423‚ 23303454‚ 23428889‚ 23648549‚ 23792462‚ 25427108‚ 25458002‚ 27220475‚ 27388993‚ 29030861‚ 32301172‚ 6147717 Comment: PM3_very_strong, PS3_moderate, PS4_moderate Number of individuals with the variant: 2
Likely Pathogenic (Mar 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Generalized pustular psoriasis (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000245625.3 First in ClinVar: Sep 14, 2015 Last updated: Apr 20, 2024	Publications: PubMed (10) PubMed: 21839423‚ 23428889‚ 23303454‚ 23648549‚ 25458002‚ 28887889‚ 27220475‚ 25427108‚ 26147717‚ 30036598 Comment: The p.Ser113Leu variant in IL36RN has been reported in >25 homozygous or compound heterozygous individuals with generalized pustular psoriasis and related psoriasis-associated pustular phenotypes. The … (more) The p.Ser113Leu variant in IL36RN has been reported in >25 homozygous or compound heterozygous individuals with generalized pustular psoriasis and related psoriasis-associated pustular phenotypes. The p.Ser113Leu variant was identified with another disease-causing variant in IL36RN in > 5 individuals (Onoufriadis 2011 PMID: 21839423, Setta-Kaffetzi 2013 PMID: 23303454, Abbas 2013 PMID: 23428889, Korber 2013 PMID: 23648549, Navarini 2015 PMID: 25427108, Hussain 2015 PMID: 25458002, Rajan 2016 PMID: 26147717, Mossner 2018 PMID: 28887889). In one report, this variant was found at a statistically significantly higher proportion of cases to controls (Twelves 2019 PMID: 30036598). It also segregated with disease in one affected sibling from one family, who had a much less severe presentation (Rajan 2016 PMID: 26147717). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 30490) and has been identified in 0.6% (412/63940) of Finnish chromosomes and 0.4% (4619/1180018) of European chromosomes, including 10 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). In vitro functional studies provide some evidence that this variant reduces protein expression and slightly reduces the inhibitory function of IL36RN (Tauber 2016 PMID: 27220475); however, the residual function may signify that this is a hypomorphic allele. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for generalized pustular psoriasis, though its high frequency in control cohorts and in unaffected homozygotes suggest that this variant is hypomorphic and may only cause disease in some cases, with specific triggers, or only mild disease in some individuals. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1, PS3_Supporting. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Acrodermatitis continua suppurativa of Hallopeau Affected status: yes Allele origin: germline	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital Accession: SCV005326330.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: The IL36RN p.Ser113Leu variant has been identified as a homozygous change or in trans with a second pathogenic IL36RN variant in multiple individuals with pustular … (more) The IL36RN p.Ser113Leu variant has been identified as a homozygous change or in trans with a second pathogenic IL36RN variant in multiple individuals with pustular psoriasis (PMID: 21839423, 23303454, 25427108 and others). It is also present in large population studies (815 heterozygous individuals, 1 homozygous individual, gnomAD v2.1.1). The relatively high frequency of this variant in the European population is thought to be due to a founder effect (PMID: 23303454). Functional studies have shown that the p.Ser113Leu variant is a hypomorphic allele that alters hydrophobic interactions within IL-36Ra as well as decreases protein levels (PMID: 27220475). Based on the ACMG/AMP guidelines, we classify the IL36RN p.Ser113Leu variant as a pathogenic change (PMID: 25741868). (less)
Uncertain significance (Mar 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000608959.31 First in ClinVar: Oct 30, 2017 Last updated: Oct 20, 2024	Number of individuals with the variant: 3
Pathogenic (Nov 01, 2013)	no assertion criteria provided Method: literature only	PSORIASIS 14, PUSTULAR Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044738.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 18, 2020	Publications: PubMed (3) PubMed: 21839423‚ 23303454‚ 23648549 Comment on evidence: In 2 probands with generalized pustular psoriasis (PSORS14; 614204), Onoufriadis et al. (2011) identified homozygosity for a 338C-T transition in the IL36RN gene, resulting in … (more) In 2 probands with generalized pustular psoriasis (PSORS14; 614204), Onoufriadis et al. (2011) identified homozygosity for a 338C-T transition in the IL36RN gene, resulting in a ser113-to-leu (S113L) substitution. A third patient was found to be compound heterozygous for S113L and a 142C-T transition in IL36RN, resulting in an arg48-to-trp (R48W; 605507.0003) substitution. Both missense substitutions affected evolutionarily conserved residues located in close proximity to critical binding residues. Functional analysis in peripheral-blood mononuclear cells demonstrated a marked increase in the production of proinflammatory cytokines after IL36A (605509) stimulation in patient cells compared to controls. The mutations segregated with disease in the families, and screening of 250 ethnically matched controls revealed 1 heterozygous carrier of S113L. Onoufriadis et al. (2011) noted that the variable age of onset of disease in the 3 affected individuals (51, 5, and 7 years) suggested a complex interaction among this major genetic determinant, potential environmental triggers, and/or additional genetic modifiers. In 5 patients with pustular psoriasis, Setta-Kaffetzi et al. (2013) identified homozygosity for the S113L mutation in IL36RN. One British patient had GPP, whereas the others were diagnosed with acral forms of pustular psoriasis, including 1 Swiss patient with acrodermatitis continua of Hallopeau and 3 British patients with palmoplantar pustulosis. In addition, 3 patients were compound heterozygous for S113L and another mutation in IL36RN: in a Malay patient with GPP, the second mutation was a splice site mutation (c.115+6T-C; 605507.0004); in a British patient with GPP, it was a lys35-to-arg (K35R; 605507.0007) substitution; and in a British patient diagnosed with acrodermatitis continua of Hallopeau, it was an arg102-to-trp (R102W; 605507.0008) substitution. In 4 patients with palmoplantar pustulosis and 1 with GPP, only a heterozygous S113L mutation was detected in the IL36RN gene; Setta-Kaffetzi et al. (2013) thus suggested that the S113L allele might have pathogenic potential even in the heterozygous state. Korber et al. (2013) identified homozygosity for the S113L mutation in the IL36RN gene in 2 patients with GPP, 1 of whom also carried a heterozygous variant in the CARD14 gene (607211). Three more patients with GPP, including 1 who also had psoriasis vulgaris (PV) and another who exhibited palmoplantar pustulosis, were compound heterozygous for S113L and another mutation in IL36RN. In 1 patient who had PV from age 10 years and developed GPP at 55 years of age, only a heterozygous S113L mutation was detected in IL36RN, but he was also found to be compound heterozygous for mutations in CARD14 (see 607211.0001). Korber et al. (2013) suggested that the CARD14 mutation was likely responsible for the long-standing PV, whereas the IL36RN mutation might have induced the development of GPP. (less)
Likely pathogenic (Oct 09, 2023)	no assertion criteria provided Method: clinical testing	Acrodermatitis continua suppurativa of Hallopeau Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004041709.1 First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023
Likely pathogenic (Aug 27, 2024)	no assertion criteria provided Method: clinical testing	IL36RN-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004115457.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The IL36RN c.338C>T variant is predicted to result in the amino acid substitution p.Ser113Leu. This variant has been reported in the homozygous and compound heterozygous … (more) The IL36RN c.338C>T variant is predicted to result in the amino acid substitution p.Ser113Leu. This variant has been reported in the homozygous and compound heterozygous states in individuals with generalized pustular psoriasis, palmarplantar pustulosis, and acrodermatitis continua of Hallopeau (Onoufriadis et al. 2011. PubMed ID: 21839423; Abbas et al. 2013. PubMed ID: 23428889; Setta-Kaffetzi et al. 2013. PubMed ID: 23303454). This variant was also identified in the heterozygous state in several individuals with generalized pustular psoriasis or palmarplantar pustulosis, suggesting that the p.Ser113Leu allele may have pathogenic potential even in the heterozygous state (Setta-Kaffetzi et al. 2013. PubMed ID: 23303454). Of note, this variant was also identified in the heterozygous state in one individual in a control cohort (Onoufriadis et al. 2011. PubMed ID: 21839423) and is reported in ~0.66% of alleles in individuals of European (Finnish) descent in gnomAD, which may be too frequent to cause disease in an autosomal dominant manner. Functional studies have shown that the p.Ser113Leu allele alters IL36RN protein expression and function (Tauber et al. 2016. PubMed ID: 27220475). Taken together, we interpret this variant as likely pathogenic for autosomal recessive disease. (less)
not provided (-)	no classification provided Method: phenotyping only	Acrodermatitis continua suppurativa of Hallopeau Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000607349.1 First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Hearing impairment (present) Age: 50-59 years Sex: male Testing laboratory: Illumina Clinical Services Laboratory,Illumina Date variant was reported to submitter: 2014-10-31 Testing laboratory interpretation: Pathogenic
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Comment:

Across a selection of the available literature, the IL36RN c.338C>T (p.Ser113Leu) missense variant has been identified in six patients in a homozygous state, in five patients in a compound heterozygous state, and in two patients in a heterozygous state. One heterozygous individual carried additional variants in the CARD14 gene (Onoufriadis et al. 2011; Setta-Kaffetzi et al. 2013; Abbas et al. 2013; Korber et al. 2013). The variant was also found in a heterozygous state in unaffected parents and was absent from 440 control individuals (Onoufriadis et al. 2011; Korber et al. 2013). This variant is reported at a frequency of 0.006635 in the European (non-Finnish) population of the Genome Aggregation Database. Two studies have evaluated the functional impact of this variant. Tauber et al. (2016) transfected the p.Ser113Leu variant form of the IL-36Ra protein into HEK293 cells and observed reduced protein expression. In addition, there was a decreased inhibitory effect on NF-kB activity compared to wild type activity. In a second study, Setta-Kaffetzi et al. (2013) used peripheral blood mononuclear cells from one patient who was homozygous for the p.Ser113Leu variant and one unrelated healthy individual and observed increased cytokine production in the presence of the variant compared to the control. Based on the collective evidence, the p.Ser113Leu variant is classified as pathogenic for generalized pustular psoriasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 113 of the IL36RN protein (p.Ser113Leu). This variant is present in population databases (rs144478519, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau (ACH) (PMID: 21839423, 23303454, 23428889, 23648549, 25427108, 25458002, 26147717, 27388993, 28887889, 30036598). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects IL36RN function (PMID: 27220475). 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.

Comment:

Common variant among individuals of European background (PMID: 24656634); Published functional studies suggest this variant results in reduced protein expression and partial impairment of capacity to repress an IL36RNmediated signaling cascade, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 27220475); 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: 25468355, 24131530, 23428889, 25458002, 25212972, 23792462, 21839423, 25989471, 22288582, 23648549, 22903787, 23303454, 23711932, 26589685, 25427108, 23909475, 23834760, 27038307, 27388993, 29030861, 30609409, 34426522, 38577038, 37414245, 26147717, 24656634, 27220475)

Comment:

The p.Ser113Leu variant in IL36RN has been reported in >25 homozygous or compound heterozygous individuals with generalized pustular psoriasis and related psoriasis-associated pustular phenotypes. The p.Ser113Leu variant was identified with another disease-causing variant in IL36RN in > 5 individuals (Onoufriadis 2011 PMID: 21839423, Setta-Kaffetzi 2013 PMID: 23303454, Abbas 2013 PMID: 23428889, Korber 2013 PMID: 23648549, Navarini 2015 PMID: 25427108, Hussain 2015 PMID: 25458002, Rajan 2016 PMID: 26147717, Mossner 2018 PMID: 28887889). In one report, this variant was found at a statistically significantly higher proportion of cases to controls (Twelves 2019 PMID: 30036598). It also segregated with disease in one affected sibling from one family, who had a much less severe presentation (Rajan 2016 PMID: 26147717). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 30490) and has been identified in 0.6% (412/63940) of Finnish chromosomes and 0.4% (4619/1180018) of European chromosomes, including 10 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). In vitro functional studies provide some evidence that this variant reduces protein expression and slightly reduces the inhibitory function of IL36RN (Tauber 2016 PMID: 27220475); however, the residual function may signify that this is a hypomorphic allele. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for generalized pustular psoriasis, though its high frequency in control cohorts and in unaffected homozygotes suggest that this variant is hypomorphic and may only cause disease in some cases, with specific triggers, or only mild disease in some individuals. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1, PS3_Supporting.

Comment:

The IL36RN p.Ser113Leu variant has been identified as a homozygous change or in trans with a second pathogenic IL36RN variant in multiple individuals with pustular psoriasis (PMID: 21839423, 23303454, 25427108 and others). It is also present in large population studies (815 heterozygous individuals, 1 homozygous individual, gnomAD v2.1.1). The relatively high frequency of this variant in the European population is thought to be due to a founder effect (PMID: 23303454). Functional studies have shown that the p.Ser113Leu variant is a hypomorphic allele that alters hydrophobic interactions within IL-36Ra as well as decreases protein levels (PMID: 27220475). Based on the ACMG/AMP guidelines, we classify the IL36RN p.Ser113Leu variant as a pathogenic change (PMID: 25741868).

Comment:

The IL36RN c.338C>T variant is predicted to result in the amino acid substitution p.Ser113Leu. This variant has been reported in the homozygous and compound heterozygous states in individuals with generalized pustular psoriasis, palmarplantar pustulosis, and acrodermatitis continua of Hallopeau (Onoufriadis et al. 2011. PubMed ID: 21839423; Abbas et al. 2013. PubMed ID: 23428889; Setta-Kaffetzi et al. 2013. PubMed ID: 23303454). This variant was also identified in the heterozygous state in several individuals with generalized pustular psoriasis or palmarplantar pustulosis, suggesting that the p.Ser113Leu allele may have pathogenic potential even in the heterozygous state (Setta-Kaffetzi et al. 2013. PubMed ID: 23303454). Of note, this variant was also identified in the heterozygous state in one individual in a control cohort (Onoufriadis et al. 2011. PubMed ID: 21839423) and is reported in ~0.66% of alleles in individuals of European (Finnish) descent in gnomAD, which may be too frequent to cause disease in an autosomal dominant manner. Functional studies have shown that the p.Ser113Leu allele alters IL36RN protein expression and function (Tauber et al. 2016. PubMed ID: 27220475). Taken together, we interpret this variant as likely pathogenic for autosomal recessive disease.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel use of Autoinflammatory Diseases Activity Index (AIDAI) captures skin and extracutaneous features to help manage pediatric DITRA: A case report and a proposal for a modified disease activity index in autoinflammatory keratinization disorders.	Stephenson C	Pediatric dermatology	2020	PMID: 32301172
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.	Ceyhan-Birsoy O	American journal of human genetics	2019	PMID: 30609409
Clinical and genetic differences between pustular psoriasis subtypes.	Twelves S	The Journal of allergy and clinical immunology	2019	PMID: 30036598
Dynamics of plasma cytokines in a patient with deficiency of interleukin-36 receptor antagonist successfully treated with anakinra.	Podlipnik S	The British journal of dermatology	2018	PMID: 29030861
The genetic basis for most patients with pustular skin disease remains elusive.	Mössner R	The British journal of dermatology	2018	PMID: 28887889
AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production.	Mahil SK	The Journal of investigative dermatology	2016	PMID: 27388993
IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype-Phenotype Correlation in Pustular Diseases.	Tauber M	The Journal of investigative dermatology	2016	PMID: 27220475
A tale of two sisters: identical IL36RN mutations and discordant phenotypes.	Rajan N	The British journal of dermatology	2016	PMID: 26147717
Palmoplantar Pustular Psoriasis Is Associated with Missense Variants in CARD14, but Not with Loss-of-Function Mutations in IL36RN in European Patients.	Mössner R	The Journal of investigative dermatology	2015	PMID: 25989471
IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis.	Hussain S	The Journal of allergy and clinical immunology	2015	PMID: 25458002
Homozygous missense mutation in IL36RN in generalized pustular dermatosis with intraoral involvement compatible with both AGEP and generalized pustular psoriasis.	Navarini AA	JAMA dermatology	2015	PMID: 25427108
Loss of IL36RN function does not confer susceptibility to psoriasis vulgaris.	Berki DM	The Journal of investigative dermatology	2014	PMID: 23792462
Mutations in IL36RN in patients with generalized pustular psoriasis.	Körber A	The Journal of investigative dermatology	2013	PMID: 23648549
Acrodermatitis continua of Hallopeau is a clinical phenotype of DITRA: evidence that it is a variant of pustular psoriasis.	Abbas O	Dermatology (Basel, Switzerland)	2013	PMID: 23428889
Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes.	Setta-Kaffetzi N	The Journal of investigative dermatology	2013	PMID: 23303454
Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.	Onoufriadis A	American journal of human genetics	2011	PMID: 21839423
Intraprostatic concentrations of ciprofloxacin after intravenous administration.	Boerema JB	Lancet (London, England)	1984	PMID: 6147717
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Text-mined citations for rs144478519 ...

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Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_012275.3(IL36RN):c.338C>T (p.Ser113Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs144478519 ...