ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.274C>T (p.Arg92Trp) (rs140630532)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000425106 SCV000516083 pathogenic not provided 2018-05-09 criteria provided, single submitter clinical testing The R92W missense variant in the AIRE gene has been reported previously in two compoundheterozygous individals with APS1 (Magitta et al., 2008). R92W was not observed with any significantfrequency in the NHLBI Exome Sequencing Project. In addition, missense variants in nearby residues(L87P, Y90C, L93R, L97P) have been reported in the Human Gene Mutation Database in association with APECED (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret this variant as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000666247 SCV000696653 pathogenic Polyglandular autoimmune syndrome, type 1 2019-02-20 criteria provided, single submitter clinical testing Variant summary: AIRE c.274C>T (p.Arg92Trp) results in a non-conservative amino acid change located in the HSR domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276962 control chromosomes (gnomAD and publication). c.274C>T has been reported in the literature in multiple affected individuals with features of Autoimmune Polyglandular Syndrome Type 1 (Zaidi_2017, Al-Mousa_2016, Magitta_2008). These data indicate that the variant is very likely to be associated with disease. The variant was also identified in our laboratory as a compound heterozygote with another variant (c.967_979delCTGTCCCCTCCGC, p.Leu323fsX51) in a patient presenting with features of hyperparathyroidism, Addisons disease, hepatitis, esophagitis, asplenia, poor dental enamel, growth hormone deficiency, and retinal dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic (1x) and once as likely pathogenic. This variant was previously classified conservatively as a VUS-possibly pathogenic variant by our laboratory in 2016. At-least two other reports reporting its presence in 4 additional affected individuals have been reported since its original classification by our laboratory. Based on all the evidence outlined above, the variant is now classified as pathogenic.
Invitae RCV000666247 SCV001405378 pathogenic Polyglandular autoimmune syndrome, type 1 2019-07-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 92 of the AIRE protein (p.Arg92Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with autoimmune polyendocrinopathy syndrome (APS) in a family and has also been observed in several individuals with APS (PMID: 18426830, 24158785, 28446514). ClinVar contains an entry for this variant (Variation ID: 379319). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000666247 SCV000790506 likely pathogenic Polyglandular autoimmune syndrome, type 1 2018-04-04 no assertion criteria provided clinical testing

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