Submissions for variant NM_000383.4(AIRE):c.1322C>T (p.Thr441Met)

gnomAD frequency: 0.00100  dbSNP: rs72650677

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000503763	SCV000051954	likely benign	not specified	2023-09-01	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.1322C>T (p.Thr441Met) results in a non-conservative amino acid change located in the Zinc finger, PHD-type domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 269480 control chromosomes, including one homozygote, predominantly at a frequency of 0.0035 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 phenotype (0.0028), while, the frequency within South Asian control individuals is equal to the estimated maximal expected allele frequency for a pathogenic variant; these data suggesting that the variant is a benign polymorphism. c.1322C>T has been reported in the literature in individuals affected with Addison disease, primary immunodeficiency disease and autoimmune thyroiditis, Sjogren syndrome and mendelian susceptibility to mycobacterial diseases (Chi_2018, Ferrera_2007, Mazza_unpublished abstract_2006. Suratannon_2020). These reports do 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. The following publications have been ascertained in the context of this evaluation (PMID: 17101293, No_PMID, 30290665, 32373116). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000503763	SCV000593079	uncertain significance	not specified	2016-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000957765	SCV001104583	benign	Polyglandular autoimmune syndrome, type 1	2024-01-31	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000957765	SCV001622932	uncertain significance	Polyglandular autoimmune syndrome, type 1	2020-07-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000957765	SCV001737193	uncertain significance	Polyglandular autoimmune syndrome, type 1	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001574716	SCV001801585	uncertain significance	not provided	2021-01-25	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported previously in a female patient with systemic sclerosis associated with autoimmune thyroiditis and Sjogren syndrome who had no features of autoimmune polyendocrinopathy syndrome (Ferrera et al., 2007), and in a patient with primary immunodeficiency disease who also harbored variants in other genes (Chi et al., 2018); This variant is associated with the following publications: (PMID: 30290665, 27266815, 17101293)
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000957765	SCV004036195	uncertain significance	Polyglandular autoimmune syndrome, type 1	2023-09-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001574716	SCV004153800	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	AIRE: PP3
GenomeConnect, ClinGen	RCV000957765	SCV001423241	not provided	Polyglandular autoimmune syndrome, type 1		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 01-09-2019 by Lab or GTR ID 1238. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.