17-80117014-TG-T

Variant names:

• chr17-80117014-TG-T
• rs777275355
• NM_000152.5:c.2242delG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PVS1 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2242del (p.Glu748ArgfsTer16) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 16 out of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One Chinese patient with late-onset Pompe disease has been described who is compound heterozygous for the variant and c.1634C>T (p.Pro545Leu). This individual has documented values showing deficiency GAA activity in dried blood spots (PMID:35071497) (PP4_Moderate). The allelic data from this individual will be used in the classification of p.Pro545Leu and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID 370639). This variant was initially classified by the ClinGen Lysosomal Diseases VCEP on Sept 07, 2021 as likely pathogenic. Recuration, on Jan 15, 2023, led to reclassification as pathogenic due to the availability of new case-level data (PMID:35071497). GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Expert Panel (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on Jan 15, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041904/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.45
• Publications: 2 publications found

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

GAA Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.2242delG	p.Glu748ArgfsTer16	frameshift	Exon 16 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2242delG	p.Glu748ArgfsTer16	frameshift	Exon 17 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2242delG	p.Glu748ArgfsTer16	frameshift	Exon 16 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.2242delG	p.Glu748ArgfsTer16	frameshift	Exon 16 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2242delG	p.Glu748ArgfsTer16	frameshift	Exon 17 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2257delG	p.Glu753ArgfsTer16	frameshift	Exon 16 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Glycogen storage disease, type II (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5

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

Other links and lift over

dbSNP: rs777275355; hg19: chr17-78090813; COSMIC: COSV56408786; COSMIC: COSV56408786;