ClinVar Genomic variation as it relates to human health

Variant summary: AAAS c.787T>C (p.Ser263Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249020 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AAAS causing Glucocorticoid Deficiency With Achalasia (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.787T>C has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Glucocorticoid Deficiency With Achalasia (example, PMID: 22538409, 18172684, 12752575). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting a mislocalization of the GFP-tagged ALADIN protein to the cytosol resulting in an inhibition of the correct targeting of ALADIN to nuclear pore complex (NPC) (example, PMID: 18172684). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 263 of the AAAS protein (p.Ser263Pro). This variant is present in population databases (rs121918550, gnomAD 0.07%). This missense change has been observed in individuals with achalasia-addisonianism-alacrimia syndrome, or triple A syndrome (PMID: 11159947, 22538409). It has also been observed to segregate with disease in related individuals. This variant is also known as c.869T>C. ClinVar contains an entry for this variant (Variation ID: 5045). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AAAS protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Published functional studies demonstrate that mutant ALADIN protein fails to localize to the nuclear membrane (PMID: 12730363, 15666842); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20931227, 12429595, 22538409, 15666842, 11159947, 26622478, 18628786, 16098009, 1537368, 6243664, 31589614, 29255950, 18172684, 12730363, 12752575)

This variant is interpreted as a Likely Pathogenic, for Achalasia-Addisonianism-Alacrima syndrome, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:11159947). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:11159947).

This variant was classified as: Pathogenic. This variant was detected in homozygous state.

The c.787T>C (p.S263P) alteration is located in coding exon 8 of the AAAS gene. This alteration results from a T to C substitution at nucleotide position 787, causing the serine (S) at amino acid position 263 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.01% (34/280414) total alleles studied. The highest observed frequency was 0.07% (18/25078) of European (Finnish) alleles. The p.S263P mutation has been reported in the homozygous and compound heterozygous states in multiple unrelated patients with triple A syndrome (Handschug, 2001; Prpic, 2003; Milenkovi, 2008; Dumic, 2012; Dumic, 2016; Kurnaz, 2018; internal data). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies demonstrated protein mislocalization in transfected HeLa cells and patient fibroblasts (Milenkovi, 2008; Jühlen, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.