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

gnomAD frequency: 0.00206  dbSNP: rs72650680

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516652	SCV000612308	uncertain significance	not specified	2016-08-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001702498	SCV000728539	likely benign	not provided	2019-10-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633447	SCV000754673	benign	Polyglandular autoimmune syndrome, type 1	2024-01-31	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.
CeGaT Center for Human Genetics Tuebingen	RCV001702498	SCV002064073	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	AIRE: BP4, BS2
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702498	SCV001931718	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001702498	SCV001964140	likely benign	not provided		no assertion criteria provided	clinical testing