ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.1249dup (p.Leu417fs) (rs786204567)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169307 SCV000220628 likely pathogenic Polyglandular autoimmune syndrome, type 1 2014-08-22 criteria provided, single submitter literature only
GeneDx RCV000320611 SCV000329057 pathogenic not provided 2016-12-16 criteria provided, single submitter clinical testing The c.1249dupC variant in the AIRE gene has been reported previously in association with APECED (Björses et al., 2000). The c.1249dupC variant causes a frameshift starting with codon Leucine 417, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 7 of the new reading frame, denoted p.Leu417ProfsX7. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1249dupC variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we consider c.1249dupC to be a pathogenic variant.
Invitae RCV000169307 SCV000944429 pathogenic Polyglandular autoimmune syndrome, type 1 2018-12-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu417Profs*7) in the AIRE gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs776437891, ExAC 0.01%). This variant has been observed in individuals and families affected with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy or autoimmune polyendocrine syndrome (PMID: 17118990, 10677297, 28919897). This variant is also known as C ins 1364-1365 in the literature. ClinVar contains an entry for this variant (Variation ID: 188935). Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). For these reasons, this variant has been classified as Pathogenic.

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