ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.3980G>A (p.Trp1327Ter) (rs267606640)

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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 RCV000435914 SCV000331819 pathogenic not provided 2016-04-15 criteria provided, single submitter clinical testing
GeneDx RCV000435914 SCV000517381 pathogenic not provided 2018-01-04 criteria provided, single submitter clinical testing The W1327X variant in the AGL gene has been reported previously in the homozygous or compoundheterozygous state in multiple individuals with GSD III (Aoyama et al., 2009; Endo et al., 2006; Lucchiari,Donati et al., 2002). This variant is predicted to cause loss of normal protein function either throughprotein truncation or nonsense-mediated mRNA decay. The W1327X variant was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. We interpretW1327X as a pathogenic variant.
Invitae RCV000333868 SCV000827885 pathogenic Glycogen storage disease type III 2019-11-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp1327*) in the AGL gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs267606640, ExAC 0.005%). This variant has been observed to be homozygous or in combination with another AGL variant in many individuals affected with glycogen storage disease (PMID: 12442284, 18924225, 16189622, 22089644, 20490926, 19834502). ClinVar contains an entry for this variant (Variation ID: 1108). Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000333868 SCV000916430 pathogenic Glycogen storage disease type III 2018-12-10 criteria provided, single submitter clinical testing Variant summary: AGL c.3980G>A (p.Trp1327X) 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.4221delA, p.Lys1407fsX8 and c.4529dupA, p.Tyr1510X). The variant allele was found at a frequency of 5.8e-05 in 276740 control chromosomes (gnomAD). c.3980G>A has been reported in the literature in multiple homozygous individuals affected with Glycogen Storage Disease Type III and indicated to be a Tunisian founder mutation (Cherif_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. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000001167 SCV000021317 pathogenic Glycogen storage disease IIIa 2009-11-01 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000333868 SCV000536862 likely pathogenic Glycogen storage disease type III 2016-09-05 no assertion criteria provided research
GenomeConnect, ClinGen RCV000333868 SCV000607271 not provided Glycogen storage disease type III no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Counsyl RCV000333868 SCV001132326 pathogenic Glycogen storage disease type III 2014-01-02 no assertion criteria provided clinical testing

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