ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.1222C>T (p.Arg408Ter) (rs113994128)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000020372 SCV000836038 pathogenic Glycogen storage disease type III 2020-09-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg408*) in the AGL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs113994128, ExAC 0.003%). This variant has been reported as a founder variant for glycogen storage disease in the Faroe islands, although it has also been reported in other populations (PMID: 11378828, 15542399, 23430490). ClinVar contains an entry for this variant (Variation ID: 1106). Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001165 SCV001363060 pathogenic Glycogen storage disease IIIa 2019-09-23 criteria provided, single submitter clinical testing Variant summary: AGL c.1222C>T (p.Arg408X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251310 control chromosomes (gnomAD). c.1222C>T has been reported in the literature as a founder mutation in the Faroe Islands, but was also found in individuals of different origin who were affected with Glycogen Storage Disease Type IIIa (Santer_2001, Sentner_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001582458 SCV001812023 pathogenic not provided 2021-02-09 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense 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: 11378828, 25525159, 31661040, 33763395, 23430490, 15542399, 26885414, 20301788, 32374048, 32623374, 33448466, 31028654, 26984562)
OMIM RCV000001165 SCV000021315 pathogenic Glycogen storage disease IIIa 2001-05-01 no assertion criteria provided literature only
GeneReviews RCV000020372 SCV000040760 pathologic Glycogen storage disease type III 2012-09-06 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000020372 SCV001454506 pathogenic Glycogen storage disease type III 2020-09-16 no assertion criteria provided clinical testing

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