rs786204678

Positions:

• chr1-99876555-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000642.3(AGL):​c.1384del​(p.Val462Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AGL NM_000642.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.41

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]

ACMG classification

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 1-99876555-TG-T is Pathogenic according to our data. Variant chr1-99876555-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.1384del	p.Val462Ter	frameshift_variant	11/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.1384del	p.Val462Ter	frameshift_variant	11/34	1	NM_000642.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251162 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135722

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461728 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727166

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Pathogenic:9

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The homozygous p.Trp461_Val462insTer variant in AGL was identified by our study in one individual with congenital myopathy (Broad Institute Rare Genomes Project). The p.Trp461_Val462insTer variant in AGL has been previously reported in 3 unrelated individuals with glycogen storage disease type III (PMID: 34649782, PMID: 20648714) but has been identified in 0.002% (1/34582) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1383849192). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These three affected individuals (PMID: 34649782, PMID: 20648714) were homozygotes, which increases the likelihood that the p.Trp461_Val462insTer variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 189080) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 461 and leads to a premature termination codon 1 amino acid downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the AGL gene is an established disease mechanism in autosomal recessive glycogen storage disease type III. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glycogen storage disease type III. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 09, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 30, 2018	Variant summary: AGL c.1384delG (p.Val462X) 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. p.Trp680X, p.Arg864X, p.Arg977X). The variant allele was found at a frequency of 4.1e-06 in 245906 control chromosomes (gnomAD). c.1384delG has been reported in the literature in homozygous individuals affected with Glycogen Storage Disease Type III (Golstein_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change creates a premature translational stop signal (p.Val462*) 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 (rs786204678, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with glycogen storage disease, type III (GSD III) (PMID: 20648714). ClinVar contains an entry for this variant (Variation ID: 189080). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 15, 2020	The p.Val462X variant in AGL has been reported in the homozygous state in 2 Latino individuals with glycogen storage disease, type III (Goldstein 2010, PMID: 20648714). It was also identified in the homozygous state through WGS by the Broad Institute Rare Genomes Project in an adult male with slowly progressive, childhood-onset muscle weakness, elevated CK, and abnormal muscle biopsy with features suggestive of possible lysosomal storage disease. This variant has been identified in 0.003% (1/34582) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant has been reported in ClinVar as pathogenic and likely pathogenic by multiple labs (Variation ID 189080). This nonsense variant leads to a premature termination codon at position 462, which is predicted to lead to a truncated or absent protein. Loss of function of the AGL gene is an established disease mechanism in autosomal recessive glycogen storage disease, type III. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glycogen storage disease, type III. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Suppporting. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs786204678; hg19: chr1-100342111;