rs748789700

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000642.3(AGL):​c.753_756del​(p.Asp251GlufsTer23) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β˜…β˜…). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

AGL
NM_000642.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.85
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-99870484-TAGAC-T is Pathogenic according to our data. Variant chr1-99870484-TAGAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 370509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGLNM_000642.3 linkuse as main transcriptc.753_756del p.Asp251GlufsTer23 frameshift_variant 6/34 ENST00000361915.8 NP_000633.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGLENST00000361915.8 linkuse as main transcriptc.753_756del p.Asp251GlufsTer23 frameshift_variant 6/341 NM_000642.3 ENSP00000355106 P1P35573-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152186
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251346
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135844
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461754
Hom.:
0
AF XY:
0.0000289
AC XY:
21
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152186
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Glycogen storage disease type III Pathogenic:11
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 09, 2018Variant summary: AGL c.753_756delCAGA (p.Asp251GlufsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (eg. c.2039G>A, p.Trp680X; c.2929C>T, p.Arg977X, c.3216_3217delGA, p.Glu1072fsX36). The variant allele was found at a frequency of 2.9e-05 in 277370 control chromosomes (gnomAD and publications). The variant, c.753_756delCAGA, has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type III in both homozygous and compound heterozygous form (Sentner_2012, Okubo_2011, Endo_2005, Li_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Sentner_2012, Li_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testing3billionMar 22, 2022Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000370509, PMID:16189622). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000357). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 21, 2019- -
Pathogenic, no assertion criteria providedclinical testingCentre for Human GeneticsAug 10, 2021disease causing -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 05, 2021- -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease Company-- -
Pathogenic, criteria provided, single submitterclinical testingCounsylFeb 26, 2016- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 12, 2020- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This sequence change creates a premature translational stop signal (p.Asp251Glufs*23) 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 (rs748789700, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with glycogen storage disease type III with or without cardiomyopathy (PMID: 16189622, 16705713, 23430490, 25431232). ClinVar contains an entry for this variant (Variation ID: 370509). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 26, 2024- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 21, 2019The c.753_756delCAGA variant (also reported as 750_753delAGA, due to alternate nomenclature) in the AGL gene has been reported previously in the homozygous state in individuals with glycogen storage disease type III (Endo et al., 2005; Sentner et al., 2012; Sentner et al., 2013). The c.753_756delCAGA variant causes a frameshift starting with codon Aspartic acid 251, changes this amino acid to a Glutamic acid residue, and creates a premature Stop codon at position 23 of the new reading frame, denoted p.Asp251GlufsX23. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.753_756delCAGA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.753_756delCAGA as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs748789700; hg19: chr1-100336040; API