ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.22C>T (p.Arg8Cys)

gnomAD frequency: 0.00001  dbSNP: rs1231469574
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668219 SCV000792787 uncertain significance Polyglandular autoimmune syndrome, type 1 2017-07-18 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000710495 SCV000840729 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000668219 SCV004297413 likely pathogenic Polyglandular autoimmune syndrome, type 1 2023-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 8 of the AIRE protein (p.Arg8Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive autoimmune polyendocrinopathy syndrome (PMID: 17118990, 27253668). ClinVar contains an entry for this variant (Variation ID: 552873). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AIRE protein function with a positive predictive value of 95%. 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.
Genomics England Pilot Project, Genomics England RCV000668219 SCV001760475 pathogenic Polyglandular autoimmune syndrome, type 1 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004754524 SCV005366224 uncertain significance AIRE-related disorder 2024-05-22 no assertion criteria provided clinical testing The AIRE c.22C>T variant is predicted to result in the amino acid substitution p.Arg8Cys. This variant has been reported in multiple individuals with autosomal recessive autoimmune polyendocrine syndrome (Table 3, Wolff et al. 2007. PubMed ID: 17118990; Bruserud et al. 2016. PubMed ID: 27253668). This variant is reported in 0.0020% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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