Submissions for variant NM_000383.4(AIRE):c.205_208dup (p.Asp70fs)

dbSNP: rs886041124

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000324168	SCV000329054	pathogenic	not provided	2016-08-22	criteria provided, single submitter	clinical testing	The c.205_208dupCAGG variant in the AIRE gene has been reported previously in patients of Arabic ancestry in association with autoimmune polyendocrinopathy syndrome, type 1 (APS1) (Heino et al., 1999; Faiyaz-Ul-Haque et al., 2009). The duplication causes a frameshift starting with codon Aspartic acid 70, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 148 of the new reading frame, denoted p.Asp70AlafsX148. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586684	SCV000696651	pathogenic	Polyglandular autoimmune syndrome, type 1	2016-03-07	criteria provided, single submitter	clinical testing	Variant summary: This c.205_208dupCAGG variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 70 and leads to a premature termination codon 148 amino acids downstream. It is predicted to cause a truncated or absent AIRE protein. Loss-of-function due to mutations in this gene is an established disease mechanism in APS1. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg257X, p.Cys311fs). This variant has been reported in multiple APS1 families in homozygous state. However, it was absent in approximately 120132 chromosomes from ExAC. One reputable database has classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000324168	SCV002069263	pathogenic	not provided	2018-09-21	criteria provided, single submitter	clinical testing	DNA sequence analysis of the AIRE gene demonstrated a four base pair duplication in exon 2, c.205_208dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 147 amino acids downstream of the mutation, p.Asp70Alafs*148. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated AIRE protein with potentially abnormal function. This pathogenic sequence change is not present in large population databases such as gnomAD, and has previously been described in patients with autoimmune polyendocrinopathy syndrome type 1 (PMIDs: 19758376, 9888391).
OMIM	RCV000586684	SCV000023638	pathogenic	Polyglandular autoimmune syndrome, type 1	2009-11-01	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000586684	SCV001469156	pathogenic	Polyglandular autoimmune syndrome, type 1	2020-11-12	no assertion criteria provided	clinical testing