rs786204645

Variant names:

• chr17-80113281-C-T
• rs786204645
• NM_000152.5:c.2104C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3 PM2_Supporting PM3_Strong PS3_Supporting PM5 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2104C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 702 (p.Arg702Cys). At least 1 patient with this variant had documented GAA deficiency with <30% of normal mean control level of GAA activity in cultured fibroblasts (PMID:14972326). At least 1 patient with this variant was reported to be on enzyme replacement therapy for Pompe disease (PMID:25687148). Other patients with this variant who were noted to have Pompe disease were found in the literature, but enzyme activity was not discussed (PMID:20308911, 31086307) (PP4_Moderate). This variant has been detected in at least 5 individuals with Pompe disease. Of those individuals, 2 were compound heterozygous for the variant and -32-13T>G a pathogenic variant by the ClinGen Lysosomal Diseases VCEP (phase unknown)(PMID:20308911, 24158270) and 1 individual was compound heterozygous for the variant and c.2481+110_2646+39del (confirmed in trans by parental/family testing)(PMID:14972326). Two individuals were homozygous for the variant (PMID:25687148, 31086307), meetings the criteria for PM3_Strong. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 (1/254192 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS resulted in less than 2% wild type GAA activity and evidence of abnormal GAA synthesis and processing, indicating that this variant may impact protein function (PMID:14972326, 19862843)(PS3_Supporting). The computational predictor REVEL gives a score of 0.985 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two different missense variants [c.2105G>T (p.Arg702Leu, ClinVar Variation ID: 92472) and c.2105G>A (p.Arg702His, ClinVar Variation ID: 426278)], in the same codon have been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 189040). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PP4_Moderate, PM3_Strong, PM2_Supporting, PS3_Supporting, PP3, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 11, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274304/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 5.87
• Publications: 13 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 11 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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.2104C>T	p.Arg702Cys	missense	Exon 15 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2104C>T	p.Arg702Cys	missense	Exon 16 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2104C>T	p.Arg702Cys	missense	Exon 15 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.2104C>T	p.Arg702Cys	missense	Exon 15 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2104C>T	p.Arg702Cys	missense	Exon 16 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2119C>T	p.Arg707Cys	missense	Exon 15 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 222816 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1448162 Hom.: 0 Cov.: 35 AF XY: 0.00000278 AC XY: 2 AN XY: 719058

African (AFR) AF: 0.00 AC: 0 AN: 33244

American (AMR) AF: 0.00 AC: 0 AN: 43062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25740

East Asian (EAS) AF: 0.00 AC: 0 AN: 39002

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83616

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1105962

Other (OTH) AF: 0.00 AC: 0 AN: 59852

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

African (AFR) AF: 0.0000483 AC: 2 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Glycogen storage disease, type II (9)
4	-	-	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		5.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.98		Gain of methylation at K697 (P = 0.0334)
MVP		1.0
MPC		0.63
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.97
Mutation Taster		=14/86	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: rs786204645; hg19: chr17-78087080;