ClinVar Miner

Submissions for variant NM_015665.6(AAAS):c.1331+1G>A (rs150511103)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254890 SCV000321309 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing The c.1331+1 G>A splice site variant has been previously reported in the homozygous state in many individuals with Allgrove syndrome (for examples, see Tullio-Pelet et al., 2000; Cherif Ben Abdallah et al., 2014; Kallabi et al., 2016). This variant destroys the canonical splice donor site in intron 14, and is expected to cause abnormal gene splicing. Functional mRNA studies show c.1331+1G>A results in skipping of exon 14 and a new stop codon in the untranslated region of the last exon of the AAAS gene (Kallabi et al., 2016). This variant is observed in 3/11576 (0.026%) alleles from individuals of Latino background in the ExAC dataset (Lek et al., 2016). Based on currently available evidence, we consider c.1331+1G>A to be pathogenic.
Invitae RCV000254890 SCV001216110 pathogenic not provided 2019-03-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 of the AAAS gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs150511103, ExAC 0.03%). This variant has been reported to be homozygous in several individuals with Allgrove syndrome, also known as Triple-A syndrome, and has been suggested to be a North African founder mutation (PMID: 11062474, 26595337, 27133709). It is also known as IVS14+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 264994). Sequencing mRNA from individuals who are homozygous for this variant has revealed multiple aberrant transcripts that would result in a frameshift (PMID: 11062474, 27414811). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000005346 SCV000025524 pathogenic Glucocorticoid deficiency with achalasia 2008-04-01 no assertion criteria provided literature only

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