Submissions for variant NM_015665.6(AAAS):c.43C>A (p.Gln15Lys)

gnomAD frequency: 0.00003  dbSNP: rs121918549

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255807	SCV000321302	pathogenic	not provided	2022-04-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate activation of a cryptic splice donor site that results in a frameshift at codon Glycine 14, changes this to a Valine residue, and creates a premature Stop codon at position 45 of the new reading frame (Krumbholz et al., 2006); also reported as p.Gly14ValfsX45; Variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11159947, 28655339, 15666842, 12730363, 22538409, 12429595, 18615337, 15217518, 11701718, 26622478, 18628786, 32185032, 31589614, 34426522, 32146693, 23073554, 16609705)
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000005347	SCV000891163	pathogenic	Glucocorticoid deficiency with achalasia	2019-03-15	criteria provided, single submitter	clinical testing	The observed variant NM_015665.6:c.43C>A/p.Gln15Lys is a missense variation found in exon 1 of the AAAS gene. It is a known pathogenic variant (dbsnp: rs121918549) and has been reported in the ExAC and gnomAD database with an allele frequency of 0.0002317 and 0.0191, respectively. The in silico prediction of this variant is disease causing by MutationTaster2. Parents of this patients are heterozygote carriers of this mutation. In summary, this variant meets the ACMG criteria to be classified as pathogenic based upon the evidence stated above.
Illumina Laboratory Services, Illumina	RCV000005347	SCV000914589	pathogenic	Glucocorticoid deficiency with achalasia	2018-08-14	criteria provided, single submitter	clinical testing	Across a selection of available literature, the AAAS c.43C>A (p.Gln15Lys) missense variant (also referred to as p.Gly14ValfsTer45) has been reported in a homozygous state in at least six individuals with achalasia-Addisonianism-alacrima syndrome (which is also referred to as triple A syndrome), and in a compound heterozygous state in at least three other affected families (Handschug et al. 2001; Sandrini et al. 2001; Houlden et al. 2002; Huebner et al. 2004; Strauss et al. 2008; Dumic et al, 2012). In at least two families who were compound heterozygous for this variant, parents were shown to be heterozygous carriers of the p.Gln15Lys variant. This variant was absent from at least 50 controls but is reported at a frequency of 0.000606 in the South Asian population from the Exome Aggregation Consortium. In fibroblasts from a patient heterozygous for the p.Gln15Lys variant, Krumbholz et al. (2006) observed two splice products after amplification from a forward primer in exon 1 and reverse primer in exon 2. They conclude that the c.43C>A variant creates a novel splice donor site resulting in a frameshift and premature truncation of the protein (referred to as p.Gly14ValfsTer45). Based on the collective evidence, the p.Gln15Lys variant is classified as pathogenic for achalasia-Addisonianism-alacrima syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255807	SCV001446774	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000005347	SCV002023802	pathogenic	Glucocorticoid deficiency with achalasia	2022-10-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000005347	SCV002547480	pathogenic	Glucocorticoid deficiency with achalasia	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: AAAS c.43C>A (p.Gln15Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic exonic 5' splice donor site located at nucleotide 41. At least one publication reports experimental evidence that this variant affects mRNA splicing due to the activation of the cryptic exonic splice donor site resulting in a frame shifted protein referred to as p.G14Vfs*45 (Krumbholz_2006). The variant allele was found at a frequency of 0.00018 in 251366 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AAAS causing Glucocorticoid Deficiency With Achalasia (0.00018 vs 0.0011), allowing no conclusion about variant significance. c.43C>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with features of Glucocorticoid Deficiency With Achalasia (also referred to as AAA syndrome) (example, Handschug_2001, Houlden_2002, Dumic_2012, Krumbholz_2006). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=5; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000005347	SCV004100376	pathogenic	Glucocorticoid deficiency with achalasia		criteria provided, single submitter	clinical testing	The missense variant p.Q15K in AAAS (NM_015665.6) (also referred to as p.Gly14ValfsTer45) has been reported both in homozygous as well as compound heterozygous state (Dumic et al,Huebner A et al,Sandrini F). Functional studies have shown that c.43 C>A activates a cryptic splice donor site (Krumbholz et al., 2006). It has been submitted to ClinVar as Pathogenic.The missense variant c.43C>A (p.Q15K) in AAAS (NM_015665.6) is observed in 17/30616 (0.0555%) alleles from individuals of South Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. In silico tools are bening in their predictions and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000255807	SCV004227263	pathogenic	not provided	2022-10-27	criteria provided, single submitter	clinical testing	PP1, PP4, PM1, PM2, PM3_strong, PS3, PS4
Invitae	RCV000255807	SCV004249147	pathogenic	not provided	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 15 of the AAAS protein (p.Gln15Lys). This variant is present in population databases (rs121918549, gnomAD 0.06%). This missense change has been observed in individual(s) with achalasia-addisonianism-alacrimia syndrome (PMID: 11159947, 22538409, 32146693). 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. ClinVar contains an entry for this variant (Variation ID: 5044). 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 not expected to disrupt AAAS protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000005347	SCV000025525	pathogenic	Glucocorticoid deficiency with achalasia	2001-11-01	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000005347	SCV001133257	uncertain significance	Glucocorticoid deficiency with achalasia	2019-09-26	flagged submission	clinical testing