Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
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). |