ClinVar Miner

Submissions for variant NM_015665.6(AAAS):c.1140_1143TCTG[1] (p.Ser382fs) (rs770214071)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255826 SCV000321308 pathogenic not provided 2015-12-15 criteria provided, single submitter clinical testing The c.1144_1147delTCTG frameshift variant in the AAAS gene has been reported previously (using alternate nomenclature) in the compound heterozygous state in a patient with Triple-A syndrome who exhibited hypoglycemic seizures with moderate achalasia, alacrima, and adrenal dysfunction (Houlden et al., 2002). The c.1144_1147delTCTG variant causes a frameshift starting with codon Serine 382, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 33 of the new reading frame, denoted p.Ser382ArgfsX33. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1144_1147delTCTG variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1144_1147delTCTG as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000778369 SCV000914587 likely pathogenic Glucocorticoid deficiency with achalasia 2017-04-28 criteria provided, single submitter clinical testing The AAAS c.1144_1147delTCTG (p.Ser382ArgfsTer33) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ser382ArgfsTer33 variant has been reported in at least two studies in which it is found in a total of two patients with achalasia-addisonianism-alacrima syndrome, including in one who was homozygous for the variant and in one who carried the variant in a compound heterozygous state with a stop-gained variant (Houlden et al. 2002; Wallace et al. 2012). The p.Ser382ArgfsTer33 variant was also identified in a heterozygous state in the unaffected parents and grandparents of the compound heterozygote. The p.Ser382ArgfsTer33variant was absent from 75 controls and is reported at a frequency of 0.00036 in the European American population of the Exome Sequencing Project. Based on the evidence from the literature and the potential impact of frameshift variants, the p.Ser382ArgfsTer33 variant is classified as a variant of uncertain 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000778369 SCV000967646 pathogenic Glucocorticoid deficiency with achalasia 2018-07-18 criteria provided, single submitter clinical testing The p.Ser382fs variant in AAAS has been reported in 1 homozygous and 1 compound heterozygous individual with Triple-A syndrome (Houlden 2002, Wallace 2012) and has been reported in ClinVar (Variation ID: 264993). This variant has been ident ified in 6/126906 European chromosomes, including 1 homozygote, by the Genome Ag gregation Database (gnomAD,; dbSNP rs770214071) . Although this variant has been seen in the general population, its frequency i s low enough to be consistent with a recessive carrier frequency, though the pre sence of a homozygous individual in the general population suggests the expressi vity of the condition may be variable. This variant is predicted to cause a fram eshift, which alters the protein?s amino acid sequence beginning at position 382 and leads to a premature termination codon 33 amino acids downstream. This alte ration is then predicted to lead to a truncated or absent protein. Loss of func tion of the AAAS gene is an established disease mechanism in autosomal recessive Triple-A syndrome. In summary, this variant meets criteria to be classified as pathogenic for Triple-A syndrome in an autosomal recessive manner. ACMG/AMP crit eria applied: PVS1, PM3, PM2_Supporting

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