ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.901G>A (p.Val301Met)

gnomAD frequency: 0.00092  dbSNP: rs150634562
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254752 SCV000321389 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing The V301M variant in the AIRE gene has been reported previously in the heterozygous state in a patient with Addison's disease and autoimmune thyroiditis, in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, and in a patient with systemic sclerosis and autoimmune thyroiditis (Soderbergh et al., 2000; Ferrera et al., 2007; Orlova et al., 2010). The V301M variant was identified in the heterozygous state in an individual with adrenal insufficiency, autoimmune thyroid disease, and primary ovarian insufficiency, however, her adult daughter was also heterozygous for V301M and had no autoimmune manifestations (Oftedal et al., 2015). These reported heterozygous cases have prompted the inclusion of V301M in several in vitro studies of AIRE, many of which have failed to show a conclusive deleterious effect for V301M (Bottomly, 2005; Chakravarty, 2009). One study did demonstrate that V301M affects expression of AIRE target genes by reducing the chromatin level interaction with its protein partners involved in transcriptional activation (Gaetani et al., 2012). The V301M variant is observed in 153/25596 (0.60%) alleles from individuals of Finnish European background, including 2 homozygous individual, in large population cohorts (Lek et al., 2016). The V301M variant is a conservative amino acid substitution, which occurs at a position in the PHD-type 1 zinc finger domain where amino acids with similar properties to Valine are tolerated across species. We interpret V301M as a variant of uncertain significance.
Eurofins Ntd Llc (ga) RCV000254752 SCV000860500 uncertain significance not provided 2018-03-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000990355 SCV001121693 likely benign Polyglandular autoimmune syndrome, type 1 2024-01-29 criteria provided, single submitter clinical testing
Mendelics RCV000990355 SCV001141303 uncertain significance Polyglandular autoimmune syndrome, type 1 2019-05-28 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003409384 SCV004115401 uncertain significance AIRE-related disorder 2023-01-21 criteria provided, single submitter clinical testing The AIRE c.901G>A variant is predicted to result in the amino acid substitution p.Val301Met. This variant has been reported in the heterozygous state in an individual with systemic sclerosis and autoimmune thyroiditis and in an individual with chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency (Ferrera F et al. 2007 PMID: 17101293; Orlova EM et al 2010. PubMed ID: 20407228). This variant has also been reported in the heterozygous state in an individual with adrenal insufficiency, autoimmune thyroid disease, and primary ovarian insufficiency, although the variant was also detected in the heterozygous state in her unaffected 30-year-old daughter (Soderbergh et al 2000. PubMed ID: 10634424, Oftedal BE et al 2015. PubMed ID: 26084028). Functional studies are inconclusive regarding the effect of this variant on protein function (Koh AS et al 2008. PubMed ID: 18840680; Oftedal BE et al 2015. PubMed ID: 26084028). This variant is reported in 0.59% of alleles in individuals of European (Finnish) descent, including one homozygous individual, in gnomAD (http://gnomad.broadinstitute.org/variant/21-45710999-G-A). This variant has also been reported in the homozygous state in a Turkish population study (Dataset S4, Kars ME et al 2021. PubMed ID: 34426522). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mayo Clinic Laboratories, Mayo Clinic RCV000254752 SCV005410143 uncertain significance not provided 2023-11-14 criteria provided, single submitter clinical testing BS2, BS3_moderate, PP3, PS3_supporting

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