ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.2039G>A (p.Trp680Ter) (rs113994129)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000578784 SCV000226440 pathogenic not provided 2014-06-13 criteria provided, single submitter clinical testing
GeneDx RCV000578784 SCV000680765 pathogenic not provided 2017-06-26 criteria provided, single submitter clinical testing The W680X nonsense variant in the AGL gene has been reported previously in association with glycogen storage disease type IIIb in an individual compound heterozygous with a pathogenic variant on the opposite allele (Shen et al., 1996). However, W680X has also been reported in four homozygous individuals with hepatomegaly, mild or no cardiac involvement, mild skeletal myopathy, and elevated CK levels, suggesting more of a type IIIa phenotype (Sentner et al., 2013). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, W680X is interpreted to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020375 SCV000918401 pathogenic Glycogen storage disease type III 2018-01-11 criteria provided, single submitter clinical testing Variant summary: The AGL c.2039G>A (p.Trp680X) variant results in a premature termination codon, predicted to cause a truncated or absent AGL protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory (c.2929C>T, p.Arg977X). One in silico tool predicts a damaging outcome for this variant. One functional study showed no GSD residual activity in GSD IIIa patients homozygous for this variant in leukocytes, fibroblasts, and/or liver tissue, and/or muscle tissue (Sentner_2012). This variant was found in 2/245574 control chromosomes in gnomAD at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGL variant (0.0022822).This variant has been reported in 4 homozygous patients of Caribbean origin with GSD IIIa (Sentner_2012) and also in one patient diagnosed with GSD type IIIb in compound heterozygosity with AGL c.16C>T (p.Gln6Ter)( Shen_AGL_JCI_1996). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000020375 SCV001224259 pathogenic Glycogen storage disease type III 2020-06-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp680*) in the AGL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs113994129, ExAC 0.003%). This variant has been observed in an individual affected with glycogen storage disease type III (GSDIII) (PMID: 8755644, 23430490). ClinVar contains an entry for this variant (Variation ID: 1096). Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000020375 SCV001441057 likely pathogenic Glycogen storage disease type III 2019-01-01 criteria provided, single submitter clinical testing
OMIM RCV000001154 SCV000021304 pathogenic Glycogen storage disease IIIb 1996-07-15 no assertion criteria provided literature only
GeneReviews RCV000020375 SCV000040763 pathologic Glycogen storage disease type III 2012-09-06 no assertion criteria provided curation Converted during submission to Pathogenic.
Institute of Human Genetics, Klinikum rechts der Isar RCV000020375 SCV001429967 pathogenic Glycogen storage disease type III 2020-06-09 no assertion criteria provided clinical testing

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