ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.3911dup (p.Asn1304fs) (rs745757264)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000412031 SCV000626744 pathogenic Glycogen storage disease type III 2020-08-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn1304Lysfs*7) in the AGL gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported as homozygous and in combination with another AGL variant in individuals affected with glycogen storage disease type III (PMID: 9584265, 23430832 , 23430832, Invitae). This variant is also known as c.3904insA in the literature. ClinVar contains an entry for this variant (Variation ID: 370832). 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 RCV000412031 SCV001363064 pathogenic Glycogen storage disease type III 2020-09-21 criteria provided, single submitter clinical testing Variant summary: AGL c.3911dupA (p.Asn1304LysfsX7) 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. The variant allele was found at a frequency of 4e-05 in 249526 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in AGL causing Glycogen Storage Disease Type III (4e-05 vs 0.0023), allowing no conclusion about variant significance. c.3911dupA (also known as c.3904insA) has been reported in the literature, in the compound heterozygous and homozygous state, in multiple individuals affected with Glycogen Storage Disease Type III (e.g. Parvari_1997, Lee_2011). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated very low enzymatic activity and glycogen accumulation in the liver, in homozygous patients (Lee_2011, Ponzi_2019). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Human Genetics RCV000412031 SCV001482490 likely pathogenic Glycogen storage disease type III 2020-08-27 criteria provided, single submitter clinical testing disease causing
Counsyl RCV000412031 SCV000486246 likely pathogenic Glycogen storage disease type III 2016-04-21 no assertion criteria provided clinical testing
Natera, Inc. RCV000412031 SCV001456552 pathogenic Glycogen storage disease type III 2020-09-16 no assertion criteria provided clinical testing

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