Submissions for variant NM_015665.6(AAAS):c.500C>T (p.Ala167Val)

dbSNP: rs1017700992

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003557743	SCV004294195	pathogenic	not provided	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 167 of the AAAS protein (p.Ala167Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with achalasia-addisonianism-alacrimia syndrome (PMID: 18953174, 21626165). It has also been observed to segregate with disease in related individuals. 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%. Experimental studies have shown that this missense change affects AAAS function (PMID: 16609705, 35570467). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Ala167 amino acid residue in AAAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30612286; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004765890	SCV005381359	pathogenic	Glucocorticoid deficiency with achalasia	2024-08-06	criteria provided, single submitter	clinical testing	Variant summary: AAAS c.500C>T (p.Ala167Val) 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 was absent in 250988 control chromosomes. c.500C>T has been reported in the literature in the homozygous state in at least 2 individuals affected with Glucocorticoid Deficiency With Achalasia, also known as AAA syndrome (example, Mochos_2011, Nakamura_2010, Salmaggi_2008). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. In vitro experiments found that this variant results in protein mislocalization (example, Macke_2022). The following publications have been ascertained in the context of this evaluation (PMID: 35570467, 21626165, 20674935, 18953174). ClinVar contains an entry for this variant (Variation ID: 2735891). Based on the evidence outlined above, the variant was classified as pathogenic.