ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.2681+1G>T

dbSNP: rs201201443
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411544 SCV000486904 pathogenic Glycogen storage disease type III 2016-08-31 criteria provided, single submitter clinical testing
Centre for Human Genetics RCV000411544 SCV001482494 pathogenic Glycogen storage disease type III 2020-06-15 criteria provided, single submitter clinical testing disease causing
Invitae RCV000411544 SCV001592637 pathogenic Glycogen storage disease type III 2023-07-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 20 of the AGL gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs201201443, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with glycogen storage disease type III (PMID: 10472540, 31028654). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 371344). Studies have shown that disruption of this splice site results in skipping of exon 21, but is expected to preserve the integrity of the reading-frame (PMID: 10472540, 31028654). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000411544 SCV002055489 pathogenic Glycogen storage disease type III 2021-07-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000411544 SCV002103550 pathogenic Glycogen storage disease type III 2022-02-08 criteria provided, single submitter clinical testing Variant summary: AGL c.2681+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250950 control chromosomes. c.2681+1G>T has been reported in the literature in the homozygous state in siblings affected with Glycogen Storage Disease Type III (Goldstein_2010, Hijazi_2021, Paschall_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000411544 SCV004211068 pathogenic Glycogen storage disease type III 2023-09-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002524625 SCV003574521 uncertain significance Inborn genetic diseases 2021-10-29 flagged submission clinical testing Resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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