Submissions for variant NM_015665.6(AAAS):c.56A>G (p.Tyr19Cys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004595136	SCV005087255	uncertain significance	Glucocorticoid deficiency with achalasia	2024-09-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with achalasia-addisonianism-alacrimia syndrome (MIM#231550). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and moderate conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported in an individual with AAAS-related features who is compound heterozygous with a splice variant (PMID: 22824007). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767582	SCV005380652	uncertain significance	not specified	2024-08-12	criteria provided, single submitter	clinical testing	Variant summary: AAAS c.56A>G (p.Tyr19Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251370 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.56A>G has been reported in the literature in individuals affected with Glucocorticoid Deficiency With Achalasia (Capataz_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22824007). ClinVar contains an entry for this variant (Variation ID: 3254953). Based on the evidence outlined above, the variant was classified as uncertain significance.