ClinVar Miner

Submissions for variant NM_012275.2(IL36RN):c.338C>T (p.Ser113Leu) (rs144478519)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513043 SCV000608959 uncertain significance not provided 2017-05-31 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000023447 SCV000607349 not provided Pustular psoriasis, generalized 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.
Illumina Clinical Services Laboratory,Illumina RCV000023447 SCV000915854 pathogenic Pustular psoriasis, generalized 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.
Invitae RCV000023447 SCV000756812 uncertain significance Pustular psoriasis, generalized 2018-10-26 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 113 of the IL36RN protein (p.Ser113Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs144478519, ExAC 0.7%) at a frequency higher than expected for a pathogenic variant. This variant has been observed in individuals and families with generalized pustular psoriasis (GPP) and/or acrodermatitis continua of Hallopeau (ACH) and has been described as a potential European founder variant (PMID: 21839423, 23303454, 25427108, 27388993, 23428889, 25458002, 23648549, 26147717, 23303454). However, this variant does not appear to be associated with palmoplantar pustulosis (PPP) and did not segregate with psoriasis vulgaris (PV) in a family (PMID: 23792462, 27542682). Experimental studies have shown that this missense change exhibits reduced capacity to inhibit NFkB activity compared to wildtype protein (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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000023447 SCV000245625 pathogenic Pustular psoriasis, generalized 2014-12-29 criteria provided, single submitter clinical testing The p.Ser113Leu (NM_012275.2 c.338C>T) variant in IL36RN has been reported in at least 10 homozygous and 6 compound heterozygous individuals with generalized pu stular psoriasis and related psoriasis-associated pustular phenotypes (Onoufriad is 2011, Setta-Kaffetzi 2013, Abbas 2013, Korber 2013). This variant has also be en identified in 0.5% (310/66,586) of European chromosomes by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144478519). Althou gh this variant has been seen in the general population, its frequency is low en ough to be consistent with a recessive carrier frequency. Biallelic variants in IL36RN have been associated with generalized pustular psoriasis. In summary, thi s variant meets our criteria to be classified as pathogenic for generalized pust ular psoriasis in an autosomal recessive manner based upon it biallelic occurren ce in patients.
OMIM RCV000023447 SCV000044738 pathogenic Pustular psoriasis, generalized 2013-11-01 no assertion criteria provided literature only

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