Submissions for variant NM_000383.4(AIRE):c.1265del (p.Pro422fs)

dbSNP: rs764878471

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255362	SCV000322390	pathogenic	not provided	2016-08-04	criteria provided, single submitter	clinical testing	The c.1265delC pathogenic variant in the AIRE gene has been reported previously in a patient with autoimmune polyendocrinopathy syndrome type 1; however, no additional variant was identified in that patient (Heino et al., 1999). The deletion causes a frameshift starting with codon Proline 422, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 58 of the new reading frame, denoted p.Pro422LeufsX58. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we consider this variant to be pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000515133	SCV000609491	pathogenic	Polyglandular autoimmune syndrome, type 1	2017-10-31	criteria provided, single submitter	clinical testing	The c.1265delC; p.Pro422LeufsTer58 variant has been reported previously in a patient with autoimmune polyendocrinopathy syndrome type 1 (AIRE); however, no additional variant was identified in that patient (Heino et al., 1999). The deletion causes a frameshift starting with codon Proline 422, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 58 of the new reading frame, denoted p.Pro422LeufsX58. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we consider this variant to be pathogenic.
Athena Diagnostics	RCV000255362	SCV000840727	pathogenic	not provided	2018-03-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000515133	SCV001361216	pathogenic	Polyglandular autoimmune syndrome, type 1	2019-10-24	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.1265delC (p.Pro422LeufsX58) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.2e-05 in 184258 control chromosomes (gnomAD). c.1265delC has been reported in the literature in individuals affected with Autoimmune Polyglandular Syndrome Type 1 (Heino_1999, Pearce_1998, Sanford_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000515133	SCV001587734	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro422Leufs*58) in the AIRE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs764878471, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with autosomal recessive autoimmune polyendocrinopathy syndrome (PMID: 9888391, 29437776). ClinVar contains an entry for this variant (Variation ID: 265456). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515133	SCV002810356	pathogenic	Polyglandular autoimmune syndrome, type 1	2022-05-19	criteria provided, single submitter	clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000515133	SCV004036177	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-09-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000515133	SCV001132331	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2015-07-17	no assertion criteria provided	clinical testing