Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001241250 | SCV001414256 | pathogenic | Polyglandular autoimmune syndrome, type 1 | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 8 of the AIRE gene. It does not directly change the encoded amino acid sequence of the AIRE protein. It affects a nucleotide within the consensus splice site. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individuals with autosomal recessive autoimmune polyendocrinopathy syndrome and/or hypoparathyroidism (PMID: 21295522, 28323927). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS8+3G>T; +5G>T. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001241250 | SCV003928955 | pathogenic | Polyglandular autoimmune syndrome, type 1 | 2023-04-12 | criteria provided, single submitter | clinical testing | Variant summary: AIRE c.995+3_995+5delinsTAT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens this site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 232740 control chromosomes (gnomAD). c.995+3_995+5delinsTAT has been reported in the literature in multiple individuals affected with Autoimmune Polyglandular Syndrome Type 1, APECED, and/or hypoparathyroidism with evidence of cosegregation with disease (Mazza_2011, Li_2017, Garelli_2021, Cranston_2022), and some patients were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |