Submissions for variant NM_000383.4(AIRE):c.342G>T (p.Lys114Asn)

gnomAD frequency: 0.00024  dbSNP: rs142788946

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797591	SCV000051957	uncertain significance	not specified	2021-11-30	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.342G>T (p.Lys114Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 246278 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 (0.00019 vs 0.0028), allowing no conclusion about variant significance. c.342G>T has been reported in the literature in one individual affected with common variable immunodeficiency (Lai_2017). The report does not provide unequivocal conclusions about association of the variant with Autoimmune Polyglandular Syndrome Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029311	SCV000951384	uncertain significance	Polyglandular autoimmune syndrome, type 1	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 114 of the AIRE protein (p.Lys114Asn). This variant is present in population databases (rs142788946, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of AIRE-related conditions (PMID: 28472507). ClinVar contains an entry for this variant (Variation ID: 35663). 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. 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.
GeneDx	RCV001546623	SCV001766169	uncertain significance	not provided	2019-06-13	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28472507)
Fulgent Genetics, Fulgent Genetics	RCV000029311	SCV002777859	uncertain significance	Polyglandular autoimmune syndrome, type 1	2022-04-20	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001546623	SCV005195166	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000029311	SCV001464456	uncertain significance	Polyglandular autoimmune syndrome, type 1	2020-04-20	no assertion criteria provided	clinical testing