Submissions for variant NM_015665.6(AAAS):c.787T>C (p.Ser263Pro)

gnomAD frequency: 0.00005  dbSNP: rs121918550

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000311283	SCV000329042	pathogenic	not provided	2016-09-27	criteria provided, single submitter	clinical testing	The S263P missense variant in the AAAS gene has been reported previously in association with triple A syndrome (Handschug et al., 2001). Serine is highly conserved at codon 263, within the third WD repeat domain (Handschug et al., 2001).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415076	SCV000492865	pathogenic	Hyperreflexia; Spastic paraparesis; Babinski sign	2014-06-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000005348	SCV000592957	likely pathogenic	Glucocorticoid deficiency with achalasia	2016-08-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624696	SCV000741936	pathogenic	Inborn genetic diseases	2022-02-14	criteria provided, single submitter	clinical testing	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.
SIB Swiss Institute of Bioinformatics	RCV000005348	SCV000803601	likely pathogenic	Glucocorticoid deficiency with achalasia	2018-05-31	criteria provided, single submitter	curation	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).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000005348	SCV001368816	pathogenic	Glucocorticoid deficiency with achalasia	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. This variant was detected in homozygous state.
Invitae	RCV000311283	SCV002235693	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	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.
MGZ Medical Genetics Center	RCV000005348	SCV002578980	likely pathogenic	Glucocorticoid deficiency with achalasia	2022-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000005348	SCV003923095	pathogenic	Glucocorticoid deficiency with achalasia	2023-03-09	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000005348	SCV000025526	pathogenic	Glucocorticoid deficiency with achalasia	2003-05-01	no assertion criteria provided	literature only