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

gnomAD frequency: 0.00264  dbSNP: rs144478519

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000023447	SCV000245625	likely pathogenic	Generalized pustular psoriasis	2024-03-31	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000513043	SCV000608959	likely pathogenic	not provided	2025-01-01	criteria provided, single submitter	clinical testing	IL36RN: PM3:Very Strong, PM2:Supporting, PS3:Supporting, BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000023447	SCV000756812	uncertain significance	Generalized pustular psoriasis	2022-10-24	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000023447	SCV000915854	pathogenic	Generalized pustular psoriasis	2018-12-07	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000513043	SCV001715715	pathogenic	not provided	2023-11-30	criteria provided, single submitter	clinical testing	PM3_very_strong, PS3_moderate, PS4_moderate
AiLife Diagnostics, AiLife Diagnostics	RCV000513043	SCV002502202	likely pathogenic	not provided	2022-03-30	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262572	SCV002543486	pathogenic	Autoinflammatory syndrome	2022-04-05	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288518	SCV002580566	uncertain significance	Acrodermatitis continua suppurativa of Hallopeau	2022-01-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000513043	SCV005078075	pathogenic	not provided	2024-06-11	criteria provided, single submitter	clinical testing	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)
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV002288518	SCV005326330	pathogenic	Acrodermatitis continua suppurativa of Hallopeau		criteria provided, single submitter	clinical testing	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).
OMIM	RCV002288518	SCV000044738	pathogenic	Acrodermatitis continua suppurativa of Hallopeau	2013-11-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000023447	SCV000607349	not provided	Generalized pustular psoriasis		no assertion provided	phenotyping only	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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV002288518	SCV004041709	likely pathogenic	Acrodermatitis continua suppurativa of Hallopeau	2023-10-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415734	SCV004115457	likely pathogenic	IL36RN-related disorder	2024-08-27	no assertion criteria provided	clinical testing	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.