chr17-80107660-C-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PM2_Supporting PM3_Strong PS3_Supporting PP4_Moderate BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.796C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 266 (p.Pro266Ser). At least seven patients with this variant and features consistent with Pompe disease have been reported. This includes 2 patients with documented laboratory values showing deficient GAA activity (<10% normal or below reference range in leukocytes) (PMID:17092519, 29124014) (PP4_Moderate). These patients are all compound heterozygous for the variant and another variant in GAA classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP, phase unknown, including c.1309C>T (p.Arg437Cys) (PMID:25526786), c.1316T>A (p.Met439Lys) (PMID:17092519, 31193175,), c.1935C>A (p.Asp645Glu) (PMID:28394184) (ClinVar# SCV002032138.1), c.546G>T (PMID:29124014) (ClinVar# SCV002032139.1), and c.1602_1605delinsAGG (p.Asn535GlyfsTer43) (PMID:28394184) (PM3_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant resulted in 14-18% wild type GAA activity, in two different studies, when expressed in COS cells. (PMID:18425781, 19862843). Western blot revealed presence of the active 76kDa GAA band, but at a much lower level than wild type (PMID:19862843). Additional variants at this amino acid positions have been reported (c.797C>T (p.Pro266Leu); c.796C>A (p.Pro266Thr) (PMID:29451150); these variants have not been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP. The score from the in silico metapredictor REVEL is 0.476 (BP4), which is a single piece of conflicting evidence in comparison with the evidence for pathogenicity. There is a ClinVar entry for this variant (Variation ID:556117, 2 star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, based on the overall evidence, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401363495/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• 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: Likely_pathogenic. The variant received 7 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.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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>T	p.Pro266Ser	missense	Exon 4 of 20	NP_000143.2
	GAA	NM_001079803.3		c.796C>T	p.Pro266Ser	missense	Exon 5 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.796C>T	p.Pro266Ser	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>T	p.Pro266Ser	missense	Exon 4 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.796C>T	p.Pro266Ser	missense	Exon 5 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.796C>T	p.Pro266Ser	missense	Exon 4 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460774 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726716

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52516

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5

Apr 12, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.796C>T (p.Pro266Ser) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250862 control chromosomes. c.796C>T has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Dec 28, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 22, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jun 03, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.796C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 266 (p.Pro266Ser). At least seven patients with this variant and features consistent with Pompe disease have been reported. This includes 2 patients with documented laboratory values showing deficient GAA activity (<10% normal or below reference range in leukocytes) (PMID: 17092519, 29124014) (PP4_Moderate). These patients are all compound heterozygous for the variant and another variant in GAA classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, phase unknown, including c.1309C>T (p.Arg437Cys) (PMID: 25526786), c.1316T>A (p.Met439Lys) (PMID: 17092519, 31193175,), c.1935C>A (p.Asp645Glu) (PMID: 28394184) (ClinVar# SCV002032138.1), c.546G>T (PMID: 29124014) (ClinVar# SCV002032139.1), and c.1602_1605delinsAGG (p.Asn535GlyfsTer43) (PMID: 28394184) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001333 (1/70356 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). This variant resulted in 14-18% wild type GAA activity, in two different studies, when expressed in COS cells. (PMID: 18425781, 19862843). Western blot revealed presence of the active 76kDa GAA band, but at a much lower level than wild type (PMID: 19862843). Additional variants at this amino acid positions have been reported (c.797C>T (p.Pro266Leu); c.796C>A (p.Pro266Thr) (PMID: 29451150); these variants have not been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP. The score from the in silico metapredictor REVEL is 0.476 (BP4), which is a single piece of conflicting evidence in comparison with the evidence for pathogenicity. There is a ClinVar entry for this variant (Variation ID:556117, 2 star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, based on the overall evidence, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 2.0.0): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, BP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 3, 2025)

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 266 of the GAA protein (p.Pro266Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 17092519, 28592009, 29124014). ClinVar contains an entry for this variant (Variation ID: 556117). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GAA protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843, 28592009). For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1

Dec 17, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 556117; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies demonstrate a damaging effect as COS-7 cells with this variant had 14% residual enzyme activity compared to wild type (Flanagan et al., 2009); This variant is associated with the following publications: (PMID: 30275481, 25526786, 20080426, 18211760, 28592009, 24169249, 29124014, 17092519, 19862843)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	9.4
DANN	Benign	0.48
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.015	N
PhyloP100		-0.0040
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.2	N
REVEL	Uncertain	0.48
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	B
Vest4		0.69
MutPred		0.74		Gain of disorder (P = 0.1168)
MVP		0.87
MPC		0.11
ClinPred		0.045	T
GERP RS		2.0
Varity_R		0.093
gMVP		0.67
Mutation Taster		=8/92	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: rs1555599667; hg19: chr17-78081459;