ClinVar Miner

Submissions for variant NM_002187.3(IL12B):c.660T>A (p.Tyr220Ter)

gnomAD frequency: 0.00004  dbSNP: rs748215576
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000779470 SCV000916098 uncertain significance Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency 2017-08-23 criteria provided, single submitter clinical testing The IL12B c.660T>A (p.Tyr220Ter) variant is a stop-gained variant, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive familial atypical mycobacteriosis.
Labcorp Genetics (formerly Invitae), Labcorp RCV000779470 SCV003457279 pathogenic Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency 2022-10-09 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 632459). This sequence change creates a premature translational stop signal (p.Tyr220*) in the IL12B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IL12B are known to be pathogenic (PMID: 11753820, 23429356). This variant is present in population databases (rs748215576, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with IL12B-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003396354 SCV004104153 likely pathogenic IL12B-related disorder 2022-08-25 criteria provided, single submitter clinical testing The IL12B c.660T>A variant is predicted to result in premature protein termination (p.Tyr220*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-158747351-A-T). Truncating variants in IL12B are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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