1-99851058-CAG-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000642.3(AGL):c.18_19delGA(p.Gln6HisfsTer20) variant causes a frameshift change. The variant allele was found at a frequency of 0.000144 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q6Q) has been classified as Likely benign.
Frequency
Consequence
NM_000642.3 frameshift
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AGL | NM_000642.3 | c.18_19delGA | p.Gln6HisfsTer20 | frameshift_variant | Exon 2 of 34 | ENST00000361915.8 | NP_000633.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251440Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135896
GnomAD4 exome AF: 0.000152 AC: 222AN: 1461662Hom.: 0 AF XY: 0.000144 AC XY: 105AN XY: 727140
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152294Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74474
ClinVar
Submissions by phenotype
Glycogen storage disease type III Pathogenic:7Other:1
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The AGL c.18_19delGA (p.Gln6HisfsTer20) variant, also referred to as c.17_18delAG, results in a frameshift, and is predicted to result in premature termination of the protein. The p.Gln6HisfsTer20 variant has been reported in at least three studies in which it is found in a total of 17 patients with glycogen storage disease type III, including in one in a homozygous state, in three in a compound heterozygous state, and in 13 in a heterozygous state where a second variant was not identified (Shen et al. 1996; Goldstein et al. 2010; Hobson-Webb et al. 2010). The p.Gln6HisfsTer20 variant was absent from 20 controls, but is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of frameshift variants, the p.Gln6HisfsTer20 variant is classified as likely pathogenic for glycogen storage disease type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
This sequence change creates a premature translational stop signal (p.Gln6Hisfs*20) 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 (rs113994127, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with glycogen storage disease III (PMID: 8755644, 20490926, 20648714). ClinVar contains an entry for this variant (Variation ID: 195097). For these reasons, this variant has been classified as Pathogenic. -
NM_000642.2(AGL):c.18_19delGA(Q6Hfs*20) is classified as likely pathogenic in the context of glycogen storage disease type III. Sources cited for classification include the following: PMID 20648714 and 8755644. Classification of NM_000642.2(AGL):c.18_19delGA(Q6Hfs*20) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Associated with GSD IIIb phenotype -
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Glycogen storage disease IIIb Pathogenic:2
Variant summary: The AGL c.18_19delGA (p.Gln6Hisfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3216_3217delGA/p.Glu1072fs). This variant is absent from 121356 control chromosomes (ExAC dataset). This variant has been reported homozygously and in compound heterozygosity in patients with clinically and biochemically confirmed dx of GSD IIIb (Goldstein_GeneticsMed_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic". Taken together, this variant is classified as pathogenic. -
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not provided Pathogenic:2
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Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34820282, 20648714, 30487145, 20301788, 20526204, 20490926, 20071996, 8755644, 31263214, 32222031, 33368379, 31589614) -
AGL-related disorder Pathogenic:1
The AGL c.18_19delGA variant is predicted to result in a frameshift and premature protein termination (p.Gln6Hisfs*20). This sequence variant has been reported to be one of the most common causative variants for glycogen storage disease (GSD) type IIIb (Shen et al. 1996. PubMed ID: 8755644; Goldstein et al. 2010. PubMed ID: 20648714). This variant has also been described in the literature as 17del and c.17_18del. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at