rs1553185403

Positions:

• chr1-99875172-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000642.3(AGL):​c.1102del​(p.Glu368LysfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGL NM_000642.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.45

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 12 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 1-99875172-TG-T is Pathogenic according to our data. Variant chr1-99875172-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 456447.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGL	NM_000642.3	c.1102del	p.Glu368LysfsTer14	frameshift_variant	9/34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.1102del	p.Glu368LysfsTer14	frameshift_variant	9/34	1	NM_000642.3	ENSP00000355106	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jun 19, 2017

Given that this type of variant results in a loss-of-function of one copy of the AGL gene, and its absence in population databases, we consider this variant pathogenic and we do feel it is suitable to offer carrier testing to relatives. The AGL gene encodes the glycogen debrancher enzyme. Two loss-of-function variants causes glycogen storage disease IIIb. At this point, we have identified ONE pathogenic variant in AGL. This does NOT give a patient a diagnosis of glycogen storage disease IIIb. Typical features of GSD IIIb are ketotic hypoglycemia in infancy and early childhood, hepatomegaly, hyperlipidemia and elevated hepatic transaminases. Hypertrophic cardiomyopathy develops during childhood which ranges from mild to severe. Skeletal myopathy is a prominent feature in the 20s and 30s. The presence of a single variant in the AGL gene is unlikely to cause heart disease in our patient. The patient was found to be a carrier by chance. This variant has not been reported in the literature; however, frameshift variants in AGL are a known mechanism of loss-of-function. This variant is not listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 40x. -

Glycogen storage disease type III Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 09, 2017

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). This sequence change deletes 1 nucleotide from exon 9 of the AGL mRNA (c.1102delG), causing a frameshift at codon 368. This creates a premature translational stop signal (p.Glu368Lysfs*14) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: -18

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553185403; hg19: chr1-100340728;