rs770590394

Variant names:

• chr17-80110736-G-A
• rs770590394
• NM_000152.5:c.1447G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PS3_Moderate PM2_Supporting PM3_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1447G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 483 (p.Gly483Arg). At least 7 individuals with this variant have been reported to have Pompe disease. Of these individuals, 3 were compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, with unknown phase, including c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (0.5 points, PMID:30214072, 33073009), c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (0.5 points, PMID:33073009), and c.32-13T>G (ClinVar Variation ID: 4027) (0.5 points, PMID:21972175, 29289479). In addition, 2 individuals were homozygous for the variant (2 x 0.5 points. PMID:36572041, Revvity Omics Clinical Laboratory data) (PM3_Strong). Two more patients have been described with the variant and another variant, either c.-32-17_-32-10delinsT CCCTGCTGAGCCTCCTACA GGCCTCCCGC (PMID:25687635) or c.569G>A (p.Arg190His) (PMID:23000108). The allelic data from these patients will be used in the classification the second variant and is not included here to avoid circular logic. At least 4 individuals have GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts / or were reported to be on enzyme replacement therapy for Pompe disease (PMIDs: 23000108, 36572041, 33073009) (PP4_Moderate). This variant has a minor allele frequency of 0.00010(1/10306) in the African population in gnomAD v2.1.1, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Expression of the variant in COS7 cells resulted in 0% GAA activity in cells and 0% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID:18425781)(PS3_Moderate). The computational predictor REVEL gives a score of 0.822 which is above the thresholds predicting a damaging (>0.7) impact on GAA function and therefore meets this criterion (PS3). There is a ClinVar entry for this variant (Variation ID: 285157). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specification of the ClinGen Lysosomal Diseases VCEP: PS3_moderate, PM2_supporting, PM3_strong, PP3, PP4_moderate.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815349/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 U:1
• Conservation: PhyloP100: 9.40
• Publications: 22 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

Our verdict: Pathogenic. The variant received 10 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.
• 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.1447G>A	p.Gly483Arg	missense	Exon 10 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1447G>A	p.Gly483Arg	missense	Exon 11 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1447G>A	p.Gly483Arg	missense	Exon 10 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.1447G>A	p.Gly483Arg	missense	Exon 10 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1447G>A	p.Gly483Arg	missense	Exon 11 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1462G>A	p.Gly488Arg	missense	Exon 10 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00000797 AC: 2 AN: 250890 AF XY: 0.00000737

Gnomad AFR exome AF: 0.0000617

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461644 Hom.: 0 Cov.: 37 AF XY: 0.0000124 AC XY: 9 AN XY: 727154

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111972

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Glycogen storage disease, type II (8)
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.82
Sift	Benign	0.030	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.98		Loss of ubiquitination at K479 (P = 0.0797)
MVP		1.0
MPC		0.59
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.96
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs770590394; hg19: chr17-78084535;