rs543360994

Variant names:

• chr17-80107645-G-A
• rs543360994
• NM_000152.5:c.781G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80107645-G-A
• chr17-80107645-G-C
• chr17-80107645-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2_Supporting PM3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.781G>A variant in GAA is a missense variant predicted to cause substitution of Ala by Thr at amino acid 261 (p.Ala261Thr). One patient with infantile-onset Pompe disease who was homozygous for this variant has been reported;, the parents were confirmed to be heterozygous (PMID 31510962) (PM3_Supporting). The patients symptoms included dyspnea, poor feeding, failure to thrive, delayed motor milestone, short PR interval, biventricular hypertrophy, and severe intellectual disability. GAA activity was 0.43% of normal (PMID 31510962)(PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (3/30616 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant results in reduced GAA activity (66% in cell extract and 5% in culture medium comparing to wildtype) and is classified as class D for the severity rating (PMID 31510962) (BS3_Supporting). The computational predictor REVEL gives a score of 0.584 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. The computational splicing predictor SpliceAI predicts no impact on splicing. Two different missense variants, c.781G>C (p.Ala261Pro) and c.782C>T (p.Ala261Val) in the same codon have been reported in patients with Pompe disease. However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is a ClinVar entry for this variant (Variation ID: 456438). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specification Version 2.0): PM2_supporting, PM3_supporting, PP4_Moderate, BS3_supporting.(Classification approved by the ClinGen LSD VCEP on Nov 1, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815016/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:4
• Conservation: PhyloP100: 9.85
• Publications: 11 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 4 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.
• PP4: 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.781G>A	p.Ala261Thr	missense_variant	Exon 4 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.781G>A	p.Ala261Thr	missense_variant	Exon 4 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152168 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251028 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460800 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 726732

African (AFR) AF: 0.0000598 AC: 2 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: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52546

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

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111862

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

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152286 Hom.: 0 Cov.: 34 AF XY: 0.0000537 AC XY: 4 AN XY: 74466

African (AFR) AF: 0.0000722 AC: 3 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

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

Jul 10, 2019

Department of Pediatrics, Division of Medical Genetics, Faculty of Medicine Ramathibodi Hospital, Mahidol University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: in vitro;research

The c.781G>A (p.A261T) is present in population database (rs543360994, ExAC 0.00002%). This variant has not been reported in the literature in individuals with GAA-related disease. ClinVar contains an entry for this variant (Variation ID: 456438). It was reported to have uncertain impact on protein function and there is no indication that it causes disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, Polyphen-2, PredictSNP2, CADD, DANN, FATHMM, and FunSeq2) all suggest that this variant is damaging/deleterious. Our study provided evident supported the impact of amino acid substitution at this position on GAA function. In vitro expression analysis of c.781G>A (p.A261T) indicates that this variant yielded partial reduction of enzyme activity and impaired GAA processing and transportation. We interpret c.781G>A (p.A261T) as a pathogenic variant. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 261 of the GAA protein (p.Ala261Thr). This variant is present in population databases (rs543360994, gnomAD 0.01%). This missense change has been observed in individual(s) with Pompe disease (PMID: 31510962). ClinVar contains an entry for this variant (Variation ID: 456438). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAA protein function. Experimental studies have shown that this missense change affects GAA function (PMID: 31510962). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Nov 01, 2022

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.781G>A variant in GAA is a missense variant predicted to cause substitution of Ala by Thr at amino acid 261 (p.Ala261Thr). One patient with infantile-onset Pompe disease who was homozygous for this variant has been reported;, the parents were confirmed to be heterozygous (PMID 31510962) (PM3_Supporting). The patients symptoms included dyspnea, poor feeding, failure to thrive, delayed motor milestone, short PR interval, biventricular hypertrophy, and severe intellectual disability. GAA activity was 0.43% of normal (PMID 31510962)(PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00010 (3/30616 alleles) in the South Asian population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant results in reduced GAA activity (66% in cell extract and 5% in culture medium comparing to wildtype) and is classified as class D for the severity rating (PMID 31510962) (BS3_Supporting). The computational predictor REVEL gives a score of 0.584 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. The computational splicing predictor SpliceAI predicts no impact on splicing. Two different missense variants, c.781G>C (p.Ala261Pro) and c.782C>T (p.Ala261Val) in the same codon have been reported in patients with Pompe disease. However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is a ClinVar entry for this variant (Variation ID: 456438). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (Specification Version 2.0): PM2_supporting, PM3_supporting, PP4_Moderate, BS3_supporting. (Classification approved by the ClinGen LSD VCEP on Nov 1, 2022). -

Nov 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

May 30, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.781G>A (p.Ala261Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain (IPR025887) of 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 allele was found at a frequency of 2e-05 in 251028 control chromosomes. c.781G>A has been observed in individual(s) affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Ngiwsara_2019). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16865695, 31510962). ClinVar contains an entry for this variant (Variation ID: 456438). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Nov 01, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;D;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.6	.;M;M
PhyloP100		9.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	.;N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	.;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.90	.;P;P
Vest4		0.61
MVP		0.98
MPC		0.35
ClinPred		0.76	D
GERP RS		5.1
Varity_R		0.67
gMVP		0.83
Mutation Taster		=30/70	disease causing

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: rs543360994; hg19: chr17-78081444; COSMIC: COSV56411108; COSMIC: COSV56411108;