ClinVar Genomic variation as it relates to human health

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.

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, http://gnomad.broadinstitute.org; 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

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21865313, 12429595, 30069287, 31589614, 34258490)

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 264993). This sequence change creates a premature translational stop signal (p.Ser382Argfs*33) 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 (rs770214071, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with triple-A syndrome (PMID: 12429595, 30069287). This variant is also known as 1226-1229delTCTG.