Submissions for variant NM_000383.4(AIRE):c.415C>T (p.Arg139Ter)

dbSNP: rs121434256

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169129	SCV000220339	pathogenic	Polyglandular autoimmune syndrome, type 1	2014-05-21	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000412909	SCV000228871	pathogenic	not provided	2014-10-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000412909	SCV000490396	pathogenic	not provided	2016-11-30	criteria provided, single submitter	clinical testing	The R139X nonsense variant has been reported previously in association with APECED (Rosatelli et al., 1998; Giordano et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, 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. Therefore, we consider the variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169129	SCV001363575	pathogenic	Polyglandular autoimmune syndrome, type 1	2019-09-05	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.415C>T (p.Arg139X) 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 2.5e-05 in 242012 control chromosomes (gnomAD). c.415C>T has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Autoimmune Polyglandular Syndrome Type 1 (e.g. Rosatelli_1998, Zaidi_2017). The variant has been found predominantly in individuals and families of Italian (Sardinian) origin therefore, suggesting it is a founder mutation. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169129	SCV001591356	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg139*) 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 (rs121434256, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with autosomal recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (PMID: 9856486, 22024611). ClinVar contains an entry for this variant (Variation ID: 3310). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000169129	SCV002517544	pathogenic	Polyglandular autoimmune syndrome, type 1	2022-05-04	criteria provided, single submitter	clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000169129	SCV004036171	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-09-14	criteria provided, single submitter	clinical testing
OMIM	RCV000169129	SCV000023632	pathogenic	Polyglandular autoimmune syndrome, type 1	2009-11-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000169129	SCV001452106	pathogenic	Polyglandular autoimmune syndrome, type 1	2020-09-16	no assertion criteria provided	clinical testing