rs777275355

Positions:

• chr17-80117014-TG-T
• chr17-80117014-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PP4_Moderate PM2_Supporting

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:3
• Conservation: PhyloP100: 9.45

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]

ACMG classification

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.2242del	p.Glu748ArgfsTer16	frameshift_variant	16/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2242del	p.Glu748ArgfsTer16	frameshift_variant	16/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 14, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jan 15, 2024	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). -

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: rs777275355; hg19: chr17-78090813;