rs1057516251

Variant names:

• chr17-80104755-C-T
• rs1057516251
• NM_000152.5:c.169C>T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.169C>T (p.Gln57Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2 (there are 20 exons in GAA), leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One individual with symptoms consistent with late-onset Pompe disease and deficient GAA activity in lymphocytes has been reported who is compound heterozygous for the variant and a missense variant, c,655G>A (p.Gly219Arg), in GAA (PMID 29124014) (PP4_Moderate). The allelic data for this patient will be used in the classification of p.Gly219Arg and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1. (PM2_Supporting). 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 Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on November 6, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041879/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 32)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 0.0610
• Publications: 4 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.169C>T	p.Gln57*	stop_gained	Exon 2 of 20	NP_000143.2
	GAA	NM_001079803.3		c.169C>T	p.Gln57*	stop_gained	Exon 3 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.169C>T	p.Gln57*	stop_gained	Exon 2 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.169C>T	p.Gln57*	stop_gained	Exon 2 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.169C>T	p.Gln57*	stop_gained	Exon 3 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.169C>T	p.Gln57*	stop_gained	Exon 2 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Glycogen storage disease, type II (5)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Benign	0.052
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.20	N
PhyloP100		0.061
Vest4		0.60
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1057516251; hg19: chr17-78078554;