17-80108603-C-T

Variant names:

• chr17-80108603-C-T
• rs776008078
• NM_000152.5:c.1190C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3 PM2_Supporting PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1190C>T variant in GAA is a missense variant predicted to cause substitution of proline by leucine at amino acid 397 (p.Pro397Leu). One patient with a diagnosis of Pompe disease has been reported with this variant, but GAA activity and clinical details were not available (PMID:30155607). This patient is compound heterozygous, phase unknown, for the variant and a variant in GAA that has been classified as likely pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1781G>A (p.Arg594His) (PMID:30155607). The variant was also found in heterozygosity in individuals identified by newborn screening who also carried pseudodeficiency variants (PMID:31076647, 34922579). Although this variant has been reported multiple times, there is currently insufficient evidence to apply either PM3 or PP4. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001865 (22/1111896 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). Expression of the variant in COS cells resulted in 0% wild type GAA activity and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe”), indicating that this variant may impact protein function (PMID:22644586) (PS3_Moderate). 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). There is a ClinVar entry for this variant (Variation ID: 456370). In summary, this variant currently meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP criteria met, based on criteria specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PS3_Moderate, PM2_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 6, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815197/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:6 U:3
• Conservation: PhyloP100: 7.29
• Publications: 8 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 4 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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.1190C>T	p.Pro397Leu	missense	Exon 7 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1190C>T	p.Pro397Leu	missense	Exon 8 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1190C>T	p.Pro397Leu	missense	Exon 7 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.1190C>T	p.Pro397Leu	missense	Exon 7 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1190C>T	p.Pro397Leu	missense	Exon 8 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1190C>T	p.Pro397Leu	missense	Exon 7 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000242 AC: 6 AN: 248010 AF XY: 0.0000297

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: 0.0000537

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460482 Hom.: 0 Cov.: 38 AF XY: 0.0000193 AC XY: 14 AN XY: 726580

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111896

Other (OTH) AF: 0.0000166 AC: 1 AN: 60352

GnomAD4 genome Cov.: 33

Alfa AF: 0.000175 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	3	-	Glycogen storage disease, type II (7)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-9.5	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.85		Loss of methylation at R393 (P = 0.0868)
MVP		1.0
MPC		0.55
ClinPred		0.97	D
GERP RS		3.4
Varity_R		0.97
gMVP		0.95
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs776008078; hg19: chr17-78082402; COSMIC: COSV56412328; COSMIC: COSV56412328;