ClinVar Miner

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

gnomAD frequency: 0.00100  dbSNP: rs72650677
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Total submissions: 7
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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 2022-05-03 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. 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
Invitae RCV000957765 SCV001104583 benign Polyglandular autoimmune syndrome, type 1 2021-12-12 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)
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.

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