ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.232T>C (p.Trp78Arg) (rs179363880)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169457 SCV000220882 likely pathogenic Polyglandular autoimmune syndrome, type 1 2014-11-14 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169457 SCV000696652 pathogenic Polyglandular autoimmune syndrome, type 1 2017-08-15 criteria provided, single submitter clinical testing Variant summary: The AIRE c.232T>C (p.Trp78Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/120322 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic AIRE variant (0.0027951). The variant has been reported in numerous affected individuals in the homozygous and compound heterozygous state and has functionally been shown to have very little transcriptional activity in transfected cells (Sparks_2016). In addition, one clinical diagnostic laboratory/reputable database classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000169457 SCV000819231 pathogenic Polyglandular autoimmune syndrome, type 1 2018-07-26 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 78 of the AIRE protein (p.Trp78Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs179363880, ExAC 0.002%). This variant has been observed to segregate with autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED) in several families (PMID: 11836330, 20718774). It has also been observed in several individuals affected with symptoms consistent with APECED (PMID: 11524733, 20407228, 15712268, 18616706). ClinVar contains an entry for this variant (Variation ID: 189060). Experimental studies have shown that this missense change disrupts AIRE protein function (PMID: 15712268). For these reasons, this variant has been classified as Pathogenic.

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