17-80117735-A-T

Variant names:

• chr17-80117735-A-T
• rs758038288
• NM_000152.5:c.2467A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2467A>T variant in GAA is a missense variant predicted to cause substitution of isoleucine by phenylalanine at amino acid 823 (p.Ile823Phe). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000002 (2/1179156 alleles) in the European, non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.918 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Although this variant has been identified in several individuals with low GAA activity on newborn screen, it not been reported in any symptomatic individuals diagnosed with Pompe disease and, as such, there is insufficient data to apply PM3 and PP4. There is a ClinVar entry for this variant (Variation ID: 456406). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PP2, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 17, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA401325518/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:5
• Conservation: PhyloP100: 3.63
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.2467A>T	p.Ile823Phe	missense	Exon 17 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2467A>T	p.Ile823Phe	missense	Exon 18 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2467A>T	p.Ile823Phe	missense	Exon 17 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.2467A>T	p.Ile823Phe	missense	Exon 17 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2467A>T	p.Ile823Phe	missense	Exon 18 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2482A>T	p.Ile828Phe	missense	Exon 17 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000415 AC: 1 AN: 240790 AF XY: 0.00000762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000933

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458014 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725186

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5572

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111156

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	-	Glycogen storage disease, type II (3)
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.78
MutPred		0.81		Loss of catalytic residue at P825 (P = 0.0271)
MVP		1.0
MPC		0.67
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.79
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs758038288; hg19: chr17-78091534;