ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.1566+8C>T (rs72650680)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516652 SCV000612308 uncertain significance not specified 2016-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000516652 SCV000728539 likely benign not specified 2018-03-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000633447 SCV000754673 benign Polyglandular autoimmune syndrome, type 1 2020-12-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000516652 SCV000918409 benign not specified 2018-08-29 criteria provided, single submitter clinical testing Variant summary: AIRE c.1566+8C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0022 in 276242 control chromosomes (3 homozygotes), predominantly within the Non-Finnish European subpopulation in the gnomAD database at a frequency of 0.0032, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 phenotype (0.0028), suggesting the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1566+8C>T in individuals affected with Autoimmune Polyglandular Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign, benign, or uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

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