17-80113282-G-C

Variant names:

• chr17-80113282-G-C
• rs398123172
• NM_000152.5:c.2105G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3 PM2_Supporting PM3_Supporting PM5

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.12105G>C variant in GAA is a missense variant predicted tocause substitution of arginine by proline at amino acid 702 (p.Arg702Pro). It has been reported in one individual in national mutation database for the country of Oman (PMID:26594346). However, no clinical details were provided and thus points can not be applied for PP4. This individual was compound heterozygous for the variant and variant classified as pathogenic by the ClinGen LD VCEP (c.2560C>T, p.Arg854Ter; ClinVar Variation ID: Variation ID: 4034, SCV001371731.1), phase unknown (PMID:26594346) (PM3_supporting). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.989 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.2105G>T, p.Arg702Leu] in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (ClinVar Variation ID: Variation ID: 92472) (PM5). There is a ClinVar entry for this variant (Variation ID: 593593). Due to insufficient evidence, this variant is classified as a variant of unknown significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): (PM5, PM3_supporting, PM2_supporting, PP3).(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA401370504/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 9.74
• Publications: 19 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 5 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.2105G>C	p.Arg702Pro	missense_variant	Exon 15 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2105G>C	p.Arg702Pro	missense_variant	Exon 15 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448060 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 719012

African (AFR) AF: 0.00 AC: 0 AN: 33242

American (AMR) AF: 0.00 AC: 0 AN: 43050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.00 AC: 0 AN: 38990

South Asian (SAS) AF: 0.00 AC: 0 AN: 83600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105906

Other (OTH) AF: 0.00 AC: 0 AN: 59856

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:2 Uncertain:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 25, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.2105G>C (p.Arg702Pro) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 222484 control chromosomes. c.2105G>C has been observed in individual(s) affected with Glycogen Storage Disease, Type 2 (Pompe Disease). Three different variants affecting the same codon have been classified as likely pathogenic/pathogenic by our lab (c.2104C>T (p.Arg702Cys), c.2105G>T (p.Arg702Leu), and c.2105G>A (p.Arg702His)) supporting the critical relevance of codon 702 to GAA protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26594346). ClinVar contains an entry for this variant (Variation ID: 593593). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Mar 05, 2024

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.12105G>C variant in GAA is a missense variant predicted to cause substitution of arginine by proline at amino acid 702 (p.Arg702Pro). It has been reported in one individual in national mutation database for the country of Oman (PMID: 26594346). However, no clinical details were provided and thus points can not be applied for PP4. This individual was compound heterozygous for the variant and variant classified as pathogenic by the ClinGen LD VCEP (c.2560C>T, p.Arg854Ter; ClinVar Variation ID: Variation ID: 4034, SCV001371731.1), phase unknown (PMID: 26594346) (PM3_supporting). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.989 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant [c.2105G>T, p.Arg702Leu] in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (ClinVar Variation ID: Variation ID: 92472) (PM5). There is a ClinVar entry for this variant (Variation ID: 593593). Due to insufficient evidence, this variant is classified as a variant of unknown significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): (PM5, PM3_supporting, PM2_supporting, PP3). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024).

not provided Pathogenic:1

Aug 16, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.0	.;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.2	H;H
PhyloP100		9.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.99
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs398123172; hg19: chr17-78087081;