ClinVar Miner

Submissions for variant NM_015665.6(AAAS):c.1058T>C (p.Ile353Thr)

dbSNP: rs765757844
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254739 SCV000321306 uncertain significance not provided 2016-01-05 criteria provided, single submitter clinical testing A I353T variant that is likely pathogenic was identified in the AAAS gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It 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. The I353T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity and size. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (L344Q) has been previously reported in association with Triple-A syndrome (Dixit et al., 2011), supporting the functional importance of this region of the protein. Therefore, this I353T variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Genetics Unit, Juan Ramón Jiménez Hospital RCV001263462 SCV001441530 likely pathogenic Glucocorticoid deficiency with achalasia 2020-05-18 no assertion criteria provided clinical testing The homozygous p.Ile353Thr variant in AAAS gene was identified in two sisters with achalasia, alacrimia, adrenal insufficiency and nasal voice. One of them has neurological manifestations (pes cavus foot, hyperreflexia, bilateral ptosis, optic atrophy, tetraparesis with predominant involvement of distal muscles, dysphagia and axonal polyneuropathy, with sensory, autonomic and mainly motor components). Their asymptomatic brother carried it in heterozygous state.

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