ClinVar Miner

Submissions for variant NM_015665.6(AAAS):c.43C>A (p.Gln15Lys) (rs121918549)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255807 SCV000321302 pathogenic not provided 2018-10-03 criteria provided, single submitter clinical testing The c.43 C>A splicing variant (also reported as Q15K) in the AAAS gene has been reported in association with Triple A syndrome (Handschug et al., 2001; Houlden et al., 2002; Strauss et al., 2008; Dumic et al., 2012; Zhang et al., 2017). Functional studies have shown that c.43 C>A activates a cryptic splice donor site (Krumbholz et al., 2006). Krumbholz et al. (2006) report that this splice site variant 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, reported as p.Gly14ValfsX45. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Based on currently available evidence, we consider c.43 C>A to be pathogenic.
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 Clinical Services Laboratory,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.
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 no assertion criteria provided clinical testing

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