ClinVar Miner

Submissions for variant NM_015665.6(AAAS):c.355C>T (p.Arg119Ter)

gnomAD frequency: 0.00001  dbSNP: rs754078574
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003332013 SCV004038508 pathogenic Glucocorticoid deficiency with achalasia 2023-08-09 criteria provided, single submitter clinical testing Variant summary: AAAS c.355C>T (p.Arg119X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 4e-06 in 250798 control chromosomes (gnomAD). c.355C>T has been reported in the literature in individuals affected with Allgrove syndrome/ Triple A syndrome (examples: Kinjo_2004 and Reshmi-Skarja_2003). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 5516781, 12548737). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003561308 SCV004294199 pathogenic not provided 2023-12-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg119*) in the AAAS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AAAS are known to be pathogenic (PMID: 11159947). This variant is present in population databases (rs754078574, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with triple A syndrome and/or Allgrove syndrome (PMID: 12548737, 15516781). This variant is also known as c.437C>T. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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