ClinVar Miner

Submissions for variant NM_000642.3(AGL):c.1735+1G>T (rs199922945)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169137 SCV000220352 likely pathogenic Glycogen storage disease type III 2014-05-27 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169137 SCV001363062 pathogenic Glycogen storage disease type III 2019-07-25 criteria provided, single submitter clinical testing Variant summary: AGL c.1735+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: three predict the variant abolishes a 5 splicing donor site; one predicts the variant weakens a 5' donor site. Following cDNA sequence analysis, Okubo_1996 reported this donor splice site variant to result in skipping of the upstream exon causing a premature termination due to frameshift. The variant allele was found at a frequency of 1.2e-05 in 251302 control chromosomes (gnomAD). c.1735+1G>T has been reported in the literature in the compound heterozygous and also homozygous state in multiple individuals affected with Glycogen Storage Disease Type III (Okubo_1996, Lu_2016, Wang_2013). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169137 SCV001381437 pathogenic Glycogen storage disease type III 2020-09-25 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 of the AGL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs199922945, ExAC 0.02%). This variant has been observed in individuals affected with glycogen storage disease type III and to segregate with disease in a family (PMID: 29614965, 8702417). ClinVar contains an entry for this variant (Variation ID: 1100). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 8702417). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). For these reasons, this variant has been classified as Pathogenic.
Centre for Human Genetics RCV000169137 SCV001482496 likely pathogenic Glycogen storage disease type III 2020-08-27 criteria provided, single submitter clinical testing disease causing
OMIM RCV000001159 SCV000021309 pathogenic Glycogen storage disease IIIa 1996-07-16 no assertion criteria provided literature only

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