Submissions for variant NM_015665.6(AAAS):c.500C>A (p.Ala167Glu)

dbSNP: rs1017700992

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413311	SCV000491738	likely pathogenic	not provided	2016-11-11	criteria provided, single submitter	clinical testing	The A167E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A167E is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a missense variant in the same residue (A167V) has been reported in the Human Gene Mutation Database in association with Triple-A syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413311	SCV003518763	pathogenic	not provided	2022-03-11	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 373167). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 167 of the AAAS protein (p.Ala167Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glucocorticoid deficiency with achalasia, also known as achalasia addisonianism alacrimia syndrome (PMID: 30612286). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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: 16609705, 18953174, 21626165). 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.