Submissions for variant NM_012275.3(IL36RN):c.115+6T>C

gnomAD frequency: 0.00021  dbSNP: rs148755083

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000033132	SCV000949734	pathogenic	Generalized pustular psoriasis	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the IL36RN gene. It does not directly change the encoded amino acid sequence of the IL36RN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs148755083, gnomAD 1.3%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with generalized pustular psoriasis (PMID: 22903787, 23303454, 23698098, 23863864, 24979538, 26589685, 28063630). It is commonly reported in individuals of Japanese and Chinese ancestry (PMID: 22903787, 23303454, 23698098, 23863864, 24979538, 26589685, 28063630). ClinVar contains an entry for this variant (Variation ID: 40005). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3 and introduces a premature termination codon (PMID: 22903787, 23698098). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV002508136	SCV001135931	pathogenic	Acrodermatitis continua suppurativa of Hallopeau	2023-03-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000033132	SCV001288877	uncertain significance	Generalized pustular psoriasis	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV000033132	SCV001739494	likely pathogenic	Generalized pustular psoriasis	2020-02-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002508136	SCV002023156	pathogenic	Acrodermatitis continua suppurativa of Hallopeau	2022-12-29	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262597	SCV002543472	likely pathogenic	Autoinflammatory syndrome	2016-12-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914894	SCV004742886	likely pathogenic	IL36RN-related disorder	2024-02-16	criteria provided, single submitter	clinical testing	The IL36RN c.115+6T>C variant is predicted to interfere with splicing. RNA studies have shown this variant leads to skipping of exon 3 (Farooq et al. 2013. PubMed ID: 22903787). This variant, in the compound heterozygous and homozygous states, has been reported to be associated with generalized pustular psoriasis with incomplete penetrance (Sugiura et al. 2012. PubMed: 23303454; Shiratori et al. 2015. PubMed ID: 25615897; Liang et al. 2017. PubMed ID: 27900482; Setta-Kaffetzi et al. 2013. PubMed ID: 23303454). This variant is reported in 1.3% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic.
OMIM	RCV002508136	SCV000056913	pathogenic	Acrodermatitis continua suppurativa of Hallopeau	2013-11-01	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000033132	SCV001142321	pathogenic	Generalized pustular psoriasis	2020-01-06	no assertion criteria provided	curation	NG_031864.1(NM_012275.2):c.115+6T>C in the IL36RN gene has an allele frequency of 0.013 in East Asian subpopulation in the gnomAD database. Farooq M et al. reported one patient with generalized pustular psoriasis was compound heterozygous for mutations c.115+6T>C and c.368C>G (p.Thr123Arg) and another was compound heterozygous for mutations c.28C>T (p.Arg10*) and c.115+6T>C in the IL36RN gene (PMID: 22903787). Shu D et al. reported two siblings with deficiency of IL-36Ra, from a Chinese Daur family, who both carried the homozygous IL36RN c.115+6T>C mutation, while other four healthy family members carried heterozygous c.115+6T>C mutations (PMID: 24979538). Experimental studies have shown that this intronic change causes skipping of exon 3, resulting in a truncated protein product (PMID: 23698098; 22903787). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP1, PP4.