ClinVar Miner

Submissions for variant NM_015665.6(AAAS):c.1300C>T (p.Arg434Ter)

gnomAD frequency: 0.00001  dbSNP: rs751369041
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000778368 SCV000914586 uncertain significance Glucocorticoid deficiency with achalasia 2017-10-03 criteria provided, single submitter clinical testing The AAAS c.1300C>T (p.Arg434Ter) variant is a stop gained variant predicted to result in premature termination of the protein. The variant has been reported in a homozygous state in one family with triple A syndrome (Krumbholz et al. 2006). Control data are unavailable for this variant, which is reported at a frequency of 0.000097 in the South Asian population of the Genome Aggregation Database. Functional studies conducted in transiently transfected HeLa cells indicate that the variant impairs protein localization, as the Arg434Ter protein was found in the cytoplasm rather than the nuclear pore like the wildtype protein (Krumbholz et al. 2006). Based on the potential impact of stop-gained variants and the limited supporting evidence from the literature, the p.Arg434Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for achalasia-addisonianism-alacrima syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV003558580 SCV004294185 pathogenic not provided 2023-03-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects AAAS function (PMID: 16609705). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 631684). This variant has not been reported in the literature in individuals affected with AAAS-related conditions. This variant is present in population databases (rs751369041, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg434*) 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).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.