ClinVar Miner

Submissions for variant NM_015665.6(AAAS):c.211del (p.His71fs)

dbSNP: rs765577880
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV003319941 SCV004024057 pathogenic not provided 2023-07-21 criteria provided, single submitter clinical testing Frameshift 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: 16098009, 15666842, 15217518, 12429595, 12548737, 33369814, 35570467)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003397000 SCV004122707 pathogenic Glucocorticoid deficiency with achalasia 2023-10-10 criteria provided, single submitter clinical testing Variant summary: AAAS c.211delC (p.His71IlefsX23) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 1.6e-05 in 251496 control chromosomes (gnomAD). c.211delC has been reported in the literature in individuals affected with Achalasia-addisonianism-alacrima syndrome (Triple-A syndrome; Macke_2022). These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 35570467). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003319941 SCV004294201 pathogenic not provided 2023-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His71Ilefs*23) in the AAAS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AAAS are known to be pathogenic (PMID: 11159947). This variant is present in population databases (rs765577880, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Achalasia-addisonianism-alacrimia syndrome (PMID: 12429595, 35570467). This variant is also known as 292 Del C. ClinVar contains an entry for this variant (Variation ID: 2575044). For these reasons, this variant has been classified as Pathogenic.

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