ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.769C>T (p.Arg257Ter) (rs121434254)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000378770 SCV000231520 pathogenic not provided 2014-10-14 criteria provided, single submitter clinical testing
GeneDx RCV000378770 SCV000329055 pathogenic not provided 2018-06-11 criteria provided, single submitter clinical testing The R257X variant in the AIRE gene has been reported previously in both the homozygous and compound heterozygous state in multiple unrelated individuals with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (Finnish-German APECED Consortium 1997; Tóth et al., 2010). The R257X variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, the R257X variant is the most common Finnish pathogenic variant, present in 82% of Finnish APECED alleles, and is also common in the Northern Italian and Eastern European APECED patient populations (Finnish-German APECED Consortium 1997; Heino et al., 2001). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay, and functional studies have demonstrated that cells transfected with the R257X allele lack expression of mRNA from AIRE-dependent genes (Oftedal et al., 2015). We interpret R257X as a pathogenic variant.
Invitae RCV000179294 SCV000832482 pathogenic Polyglandular autoimmune syndrome, type 1 2018-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg257*) in the AIRE gene. It is expected to result in an absent or disrupted protein product. This variant is present in the Finnish sub-population of the gnomAD database at a relatively high frequency (0.5%), although it has been demonstrated to be a founder mutation in this population (PMID: 9398840). In addition to the Finnish population, this variant has also been found to be compound heterozygous or homozygous in individuals of other ethnicities with Autoimmune-Poly-Endocrinopathy-Candidiasis Ectoderma Dystrophy (APECED) (PMID: 9398840, 20718774, 22024611). ClinVar contains an entry for this variant (Variation ID: 3307). Experimental studies have shown that this nonsense change, p.Arg257*, abolishes transcriptional regulation of the AIRE-regulated gene, KRT14, and that this variant behaves in a strictly autosomal recessive manner (PMID: 26084028). Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000378770 SCV000840731 pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing
OMIM RCV000179294 SCV000023628 pathogenic Polyglandular autoimmune syndrome, type 1 2009-11-01 no assertion criteria provided literature only
Counsyl RCV000179294 SCV000485165 pathogenic Polyglandular autoimmune syndrome, type 1 2016-03-11 no assertion criteria provided clinical testing

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