rs1555599667

Variant names:

• chr17-80107660-C-A
• rs1555599667
• NM_000152.5:c.796C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80107660-C-A
• chr17-80107660-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2_Supporting PM3_Supporting PM5_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.796C>A variant in GAA is a missense variant predicted to cause substitution of proline by threonine at amino acid 266 (p.Pro266Thr). One patient with a diagnosis of Pompe disease has been reported who is compound heterozygous, phase unknown, for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.2237G>A (p.Trp746Ter) (PMID:29451150) (PM3_Supporting). Two other missense changes, c.796C>T (p.Pro266Ser) and c.797C>T (p.Pro266Leu) at the same amino acid residue have been reported. The first, c.796C>T (p.Pro266Ser), has been classified as likely pathogenic by the ClinGen LSD VCEP. The second variant, c.797C>T (p.Pro266Leu), has not been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5_Supporting). The computational predictor REVEL gives a score of 0.262 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There is no ClinVar entry for this variant.In summary, this variant meet the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP codes met, based on the specifications of the ClinGen LSD VCEP (Specifications version 2.0): PM2_Supporting, PM3_Supporting, PM5_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401363493/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 34)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: -0.00400
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.796C>A	p.Pro266Thr	missense	Exon 4 of 20	NP_000143.2
	GAA	NM_001079803.3		c.796C>A	p.Pro266Thr	missense	Exon 5 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.796C>A	p.Pro266Thr	missense	Exon 4 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.796C>A	p.Pro266Thr	missense	Exon 4 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.796C>A	p.Pro266Thr	missense	Exon 5 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.796C>A	p.Pro266Thr	missense	Exon 4 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:1

Jun 03, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.796C>A variant in GAA is a missense variant predicted to cause substitution of proline by threonine at amino acid 266 (p.Pro266Thr). One patient with a diagnosis of Pompe disease has been reported who is compound heterozygous, phase unknown, for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.2237G>A (p.Trp746Ter) (PMID: 29451150) (PM3_Supporting). Two other missense changes, c.796C>T (p.Pro266Ser) and c.797C>T (p.Pro266Leu) at the same amino acid residue have been reported. The first, c.796C>T (p.Pro266Ser), has been classified as likely pathogenic by the ClinGen LD VCEP. The second variant, c.797C>T (p.Pro266Leu), has not yet been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP (PM5_Supporting). Expression of the variant in HEK293 cells demonstrates loss of GAA activity, and western blot shows only the 110kDa precursor band suggesting abnormal GAA processing (using the assay reported in PMID: 36246652). The computational predictor REVEL gives a score of 0.262 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There is a ClinVar entry for this variant (Variation ID: 1693549). In summary, this variant meet the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG/AMP codes met, based on the specifications of the ClinGen LD VCEP (Specifications Version 2.0.0): PS3_Moderate, PM2_Supporting, PM3_Supporting, PM5_Supporting, BP4.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	0.0012	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Benign	0.66
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.0040
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.26
Sift	Benign	0.51	T
Sift4G	Uncertain	0.060	T
Polyphen		0.018	B
Vest4		0.43
MutPred		0.42		Gain of catalytic residue at P266 (P = 0.0155)
MVP		0.92
MPC		0.14
ClinPred		0.18	T
GERP RS		2.0
Varity_R		0.12
gMVP		0.72
Mutation Taster		=12/88	disease causing

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: rs1555599667; hg19: chr17-78081459;