ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.753_756del (p.Asp251fs) (rs748789700)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409582 SCV000485852 pathogenic Glycogen storage disease type III 2016-02-26 criteria provided, single submitter clinical testing
Invitae RCV000409582 SCV000626766 pathogenic Glycogen storage disease type III 2020-10-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp251Glufs*23) in the AGL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs748789700, ExAC 0.01%). This variant has been reported in individuals affected with glycogen storage disease type III with cardiomyopathy in two cases (PMID: 16189622, 16705713, 23430490, 25431232). ClinVar contains an entry for this variant (Variation ID: 370509). 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 RCV000409582 SCV000918404 pathogenic Glycogen storage disease type III 2018-08-09 criteria provided, single submitter clinical testing Variant summary: AGL c.753_756delCAGA (p.Asp251GlufsX23) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2039G>A, p.Trp680X; c.2929C>T, p.Arg977X, c.3216_3217delGA, p.Glu1072fsX36). The variant allele was found at a frequency of 2.9e-05 in 277370 control chromosomes (gnomAD and publications). The variant, c.753_756delCAGA, has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type III in both homozygous and compound heterozygous form (Sentner_2012, Okubo_2011, Endo_2005, Li_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Sentner_2012, Li_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001008814 SCV001168615 pathogenic not provided 2019-03-21 criteria provided, single submitter clinical testing The c.753_756delCAGA variant (also reported as 750_753delAGA, due to alternate nomenclature) in the AGL gene has been reported previously in the homozygous state in individuals with glycogen storage disease type III (Endo et al., 2005; Sentner et al., 2012; Sentner et al., 2013). The c.753_756delCAGA variant causes a frameshift starting with codon Aspartic acid 251, changes this amino acid to a Glutamic acid residue, and creates a premature Stop codon at position 23 of the new reading frame, denoted p.Asp251GlufsX23. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.753_756delCAGA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.753_756delCAGA as a pathogenic variant.
Centogene AG - the Rare Disease Company RCV000409582 SCV001424356 pathogenic Glycogen storage disease type III criteria provided, single submitter clinical testing

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