17-80117020-G-T

Position:

• chr17-80117020-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2242G>T (p.Glu748Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 16/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with this variant, diagnosed with late onset Pompe disease, has been reported (PMID:31545528). This individual is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PMID:31545528) (PM3_Supporting). The data are insufficient to apply PP4 based on the specifications of the ClinGen Lysosomal Diseases VCEP. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID 370268). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, April 11, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041903/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 0.773

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 10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2242G>T	p.Glu748Ter	stop_gained	16/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2242G>T	p.Glu748Ter	stop_gained	16/20	1	NM_000152.5	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	Oct 24, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 29, 2015	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Apr 11, 2023	The NM_000152.5:c.2242G>T (p.Glu748Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 16/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient with this variant, diagnosed with late onset Pompe disease, has been reported (PMID: 31545528). This individual is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PMID: 31545528) (PM3_Supporting). The data are insufficient to apply PP4 based on the specifications of the ClinGen Lysosomal Diseases VCEP. The variant is absent in gnomAD v2.1.1. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID 370268). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, April 11, 2023). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.13	N
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1057516363; hg19: chr17-78090819;