ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.1244A>G (p.His415Arg)

gnomAD frequency: 0.00017  dbSNP: rs149609996
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000822212 SCV000963003 uncertain significance Polyglandular autoimmune syndrome, type 1 2022-10-24 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 415 of the AIRE protein (p.His415Arg). This variant is present in population databases (rs149609996, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with AIRE-related conditions. ClinVar contains an entry for this variant (Variation ID: 664176). 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 not expected to disrupt AIRE protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetic Services Laboratory, University of Chicago RCV001816907 SCV002066214 uncertain significance not specified 2020-08-17 criteria provided, single submitter clinical testing DNA sequence analysis of the AIRE gene demonstrated a sequence change, c.1244A>G, in exon 10 that results in an amino acid change, p.His415Arg. This sequence change does not appear to have been previously described in patients with AIRE-related disorders and has been described in the gnomAD database with a low population frequency of 0.030% in non-Finnish European subpopulation (dbSNP rs149609996). The p.His415Arg change affects a poorly conserved amino acid residue located in a domain of the AIRE protein that is known to be functional. The p.His415Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.His415Arg change remains unknown at this time.
Fulgent Genetics, Fulgent Genetics RCV000822212 SCV002784429 uncertain significance Polyglandular autoimmune syndrome, type 1 2021-07-15 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000822212 SCV003823081 uncertain significance Polyglandular autoimmune syndrome, type 1 2021-06-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000822212 SCV001464223 uncertain significance Polyglandular autoimmune syndrome, type 1 2020-01-24 no assertion criteria provided clinical testing

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