Submissions for variant NM_173842.3(IL1RN):c.63A>G (p.Ser21=)

gnomAD frequency: 0.00002  dbSNP: rs763872895

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779276	SCV000915855	uncertain significance	Sterile multifocal osteomyelitis with periostitis and pustulosis	2017-07-20	criteria provided, single submitter	clinical testing	The IL1RN c.74-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance, but suspicious for pathogenicity for interleukin 1 receptor antagonist deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000779276	SCV004281830	likely pathogenic	Sterile multifocal osteomyelitis with periostitis and pustulosis	2024-08-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the IL1RN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IL1RN are known to be pathogenic (PMID: 19494218, 21792839, 22940634, 26100510). This variant is present in population databases (rs763872895, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with IL1RN-related conditions. ClinVar contains an entry for this variant (Variation ID: 559539). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology	RCV000677223	SCV000803357	uncertain significance	Interstitial lung disease 2	2018-05-06	no assertion criteria provided	case-control