rs113994129
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000642.3(AGL):c.2039G>A(p.Trp680Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000642.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGL | NM_000642.3 | c.2039G>A | p.Trp680Ter | stop_gained | 16/34 | ENST00000361915.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGL | ENST00000361915.8 | c.2039G>A | p.Trp680Ter | stop_gained | 16/34 | 1 | NM_000642.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250658Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135498
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461770Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727180
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74332
ClinVar
Submissions by phenotype
Glycogen storage disease type III Pathogenic:8Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 23, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 12, 2023 | - - |
not provided, no classification provided | literature only | GeneReviews | - | 2039G>A, 2590C>T and 3682C>T are 3 common variants that together account for approximately 28% of pathogenic variants in persons of European origin. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 11, 2018 | Variant summary: The AGL c.2039G>A (p.Trp680X) variant results in a premature termination codon, predicted to cause a truncated or absent AGL protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory (c.2929C>T, p.Arg977X). One in silico tool predicts a damaging outcome for this variant. One functional study showed no GSD residual activity in GSD IIIa patients homozygous for this variant in leukocytes, fibroblasts, and/or liver tissue, and/or muscle tissue (Sentner_2012). This variant was found in 2/245574 control chromosomes in gnomAD at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic AGL variant (0.0022822).This variant has been reported in 4 homozygous patients of Caribbean origin with GSD IIIa (Sentner_2012) and also in one patient diagnosed with GSD type IIIb in compound heterozygosity with AGL c.16C>T (p.Gln6Ter)( Shen_AGL_JCI_1996). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 27, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Trp680*) in the AGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). This variant is present in population databases (rs113994129, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type III (GSDIII) (PMID: 8755644, 23430490). ClinVar contains an entry for this variant (Variation ID: 1096). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 09, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2017 | The W680X nonsense variant in the AGL gene has been reported previously in association with glycogen storage disease type IIIb in an individual compound heterozygous with a pathogenic variant on the opposite allele (Shen et al., 1996). However, W680X has also been reported in four homozygous individuals with hepatomegaly, mild or no cardiac involvement, mild skeletal myopathy, and elevated CK levels, suggesting more of a type IIIa phenotype (Sentner et al., 2013). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, W680X is interpreted to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Feb 09, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 13, 2014 | - - |
Glycogen storage disease IIIb Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 15, 1996 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at