rs369973784
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000642.3(AGL):βc.4260-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000714 in 1,581,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.000059 ( 0 hom., cov: 32)
Exomes π: 0.000073 ( 0 hom. )
Consequence
AGL
NM_000642.3 intron
NM_000642.3 intron
Scores
2
Splicing: ADA: 0.9980
2
Clinical Significance
Conservation
PhyloP100: 0.224
Genes affected
AGL (HGNC:321): (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) This gene encodes the glycogen debrancher enzyme which is involved in glycogen degradation. This enzyme has two independent catalytic activities which occur at different sites on the protein: a 4-alpha-glucotransferase activity and a amylo-1,6-glucosidase activity. Mutations in this gene are associated with glycogen storage disease although a wide range of enzymatic and clinical variability occurs which may be due to tissue-specific alternative splicing. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-99916398-A-G is Pathogenic according to our data. Variant chr1-99916398-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99916398-A-G is described in Lovd as [Pathogenic]. Variant chr1-99916398-A-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| AGL | NM_000642.3 | c.4260-12A>G | intron_variant | ENST00000361915.8 | NP_000633.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000591 AC: 9AN: 152176Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000575 AC: 14AN: 243346Hom.: 0 AF XY: 0.0000533 AC XY: 7AN XY: 131258
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GnomAD4 exome AF: 0.0000727 AC: 104AN: 1429820Hom.: 0 Cov.: 28 AF XY: 0.0000716 AC XY: 51AN XY: 712436
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GnomAD4 genome 0.0000591 AC: 9AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74352
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:16Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Glycogen storage disease type III Pathogenic:10Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 31, 2019 | Variant summary: AGL c.4260-12A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3 acceptor site. Three predict the variant creates a cryptic 3 acceptor site. At least two publication reports this variant created a new 3' splice site and resulted in insertion of an 11-bp intron sequence between exon 32 and exon 33 in the patients debrancher mRNA. The predicted mutant enzyme was truncated by 112 amino acids as a result of premature termination (p.Phe1420Hisfs*16) (Okubo_1998, Shaiu_2000). The variant allele was found at a frequency of 5.8e-05 in 243346 control chromosomes (gnomAD). c.4260-12A>G has been reported in the literature in multiple individuals in compound heterozygous or homozygous states affected with Glycogen Storage Disease Type III (Okubo_1998, Shaiu_2000, Lu_2016, Sentner_2012). These data indicate that the variant is very likely to be associated with disease. At least two publication reports this variant had an impact on protein function and debrancher activity in a liver specimen was reduced to less than 30% of the control value (Okubo_1998, Shaiu_2000). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 20, 2024 | This sequence change falls in intron 31 of the AGL gene. It does not directly change the encoded amino acid sequence of the AGL protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs369973784, gnomAD 0.02%). This variant has been observed in individuals with glycogen storage disease type III (GSDIII) (PMID: 9490286, 10655153, 11924557, 20648714, 22089644, 23430490, 25827695). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS32-12A>G. ClinVar contains an entry for this variant (Variation ID: 1099). Studies have shown that this variant results in 11 nucleotide insertion and introduces a premature termination codon (PMID: 9490286). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
| not provided, no classification provided | literature only | GeneReviews | - | Associated with milder phenotype - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 12, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 20, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 21, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 30, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 07, 2022 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 13, 2014 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2023 | Published functional studies demonstrate a damaging effect (Okubo et al., 1998); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 9490286, 33763395, 31589614, 34820282, 25827695) - |
| Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 09, 2018 | - - |
Glycogen storage disease IIIb Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2000 | - - |
Glycogen storage disease IIIa Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2000 | - - |
AGL-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 10, 2023 | The AGL c.4260-12A>G variant is predicted to interfere with splicing. This variant has been reported, homozygous, in four families with multiple affected individuals with glycogen storage disease type 3 (GSD III). Haplotype analysis showed that this variant is a founder mutation in Saudia Arabia and cDNA sequence analysis showed that it leads to a truncated protein (Basit et al. 2014. PubMed ID: 25827695). Itβs also been reported in the homozygous and compound heterozygous state in multiple unrelated patients, including one patient who showed excessive accumulation of glycogen in the liver (Okubo et al. 1998. PubMed ID: 9490286, Hijazi et al. 2021. PubMed ID: 34820282, Table S1 - Fang et al. 2021. PubMed ID: 33763395). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-100381954-A-G). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
DS_AL_spliceai
Position offset: 12
Find out detailed SpliceAI scores and Pangolin per-transcript scores at