Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000724650 | SCV000331829 | pathogenic | not provided | 2016-07-11 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000377764 | SCV000626705 | pathogenic | Glycogen storage disease type III | 2023-12-14 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 20 of the AGL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with glycogen storage disease (PMID: 10472540, 16705713). ClinVar contains an entry for this variant (Variation ID: 281229). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000377764 | SCV001338430 | pathogenic | Glycogen storage disease type III | 2020-04-24 | criteria provided, single submitter | clinical testing | Variant summary: AGL c.2681+1G>A 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. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in exon 21 skipping (Hadjigeorgiou_AGL_JIMD_1999). The variant allele was found at a frequency of 3.2e-05 in 251020 control chromosomes (gnomAD). c.2681+1G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type III (Hadjigeorgiou_1999, Lucchiari_2007). These data indicate that the variant is very likely to be associated with disease. AGL activity and protein were found to be almost absent in patients muscle specimens (Hadjigeorgiou_1999). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Genome- |
RCV000377764 | SCV002055490 | pathogenic | Glycogen storage disease type III | 2021-07-15 | criteria provided, single submitter | clinical testing | |
3billion | RCV000377764 | SCV002572901 | pathogenic | Glycogen storage disease type III | 2022-09-01 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000281229). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
Fulgent Genetics, |
RCV000377764 | SCV002780805 | pathogenic | Glycogen storage disease type III | 2022-02-08 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV003401231 | SCV004105908 | pathogenic | AGL-related condition | 2022-11-16 | criteria provided, single submitter | clinical testing | The AGL c.2681+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous and compound heterozygous states in individuals with glycogen storage disease III (Patient 2, Hadjigeorgiou et al. 1999. PubMed ID: 10472540; Lucchiari et al. 2006. PubMed ID: 16705713; Abdullah et al. 2019. PubMed ID: 31028654). This variant was also reported in the heterozygous state in an individual with glycogen storage disease III and was also identified in that patient's affected sister (Patient 3, Hadjigeorgiou et al. 1999. PubMed ID: 10472540). Functional studies have shown that the c.2681+1G>A variant leads to abnormal splicing (Hadjigeorgiou et al. 1999. PubMed ID: 10472540; Abdullah et al. 2019. PubMed ID: 31028654). Of note, another variant impacting the same splice site, c.2681+1G>T, has also been reported in individuals with glycogen storage disease III (Goldstein et al. 2010. PubMed ID: 20648714; Supplemental Table S2, Hijazi et al. 2021. PubMed ID: 34820282). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-100350260-G-A). Variants that disrupt the consensus splice donor site in AGL are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. |
Counsyl | RCV000377764 | SCV001132327 | pathogenic | Glycogen storage disease type III | 2014-01-02 | no assertion criteria provided | clinical testing |