chr17-80112929-G-A

Variant names:

• chr17-80112929-G-A
• rs536906561
• NM_000152.5:c.1942G>A

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3 PM3 PM2_Supporting PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1942G>A (p.Gly648Ser) variant in GAA is a missense variant with a highest population minor allele frequency in gnomAD v2.1.1 of 0.00034 (10/29720 alleles) in the S. Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). At least 18 patients with a diagnosis of Pompe disease have been reported with this variant including those with documented deficient GAA activity and/or symptoms consistent with infantile onset Pompe disease and/or on enzyme replacment therapy (PMIDs 9535769, 17573812, 26497565, 29422078, 30214072, 31510962) (PP4_Moderate). In a study of the Maroon population of French Guiana, 9 out of 15 probands with "enzymatically confirmed" infantile onset Pompe disease were compound heterozygous for c.1942G>A (p.Gly648Ser) and c.2560C>T (p.Arg854Ter), a variant which has been classified as pathogenic by the ClinGen LD VCEP. The two variants are assumed to be in trans based on the high carrier frequency of both variants in that population. The carrier frequency of c.1942G>A (p.Gly648Ser) was 1 in 47 (9/425 women tested) (PMID:29637184). Patients have also been reported who are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.2214G>A (p.Trp768Ter) (PMID:26575883) and c.-32-13T>G (2 patients, PMIDs: 17643989, 25455803, 27193587). In addition, at least 3 patients are homozygous for the variant (PMID:26497565, 29122469, 29889338, 30214072) (PM3_VeryStrong). Patients compound heterozygous for the variant and c.1076-22T>G (17643989, 25455803), c.2646+2T>A (PMID:29422078), and c.1099T>C (p.Trp367Arg) (PMID:31510962) have also been reported. However, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid circular logic. When expressed in SV40_immortalized GAA deficient fibroblasts, the enzyme activity was "negligible" (PMID:9535769), and when expressed in COS cells, the variant resulted in <2% wild type GAA activity (PMID:19862843) (PS3_Supporting). The score for the REVEL meta-predictor, 0.98, also supports that the variant has a deleterious impact on GAA function (PP3). Another amino acid substitution at the same position has been reported in at least one individual with Pompe disease c.1943G>A (p.Gly648Asp) (PMIDs 22644586, 23146291, 23843830) (note that this data will be used in the classification of p.Gly648Asp and was not used here in order to avoid a circular argument). There is a ClinVar entry for this variant (Variation ID: 188902). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, July 3, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274102/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 9.82
• Publications: 27 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 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.
• 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.1942G>A	p.Gly648Ser	missense	Exon 14 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1942G>A	p.Gly648Ser	missense	Exon 15 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1942G>A	p.Gly648Ser	missense	Exon 14 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.1942G>A	p.Gly648Ser	missense	Exon 14 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1942G>A	p.Gly648Ser	missense	Exon 15 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1957G>A	p.Gly653Ser	missense	Exon 14 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152174 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000536 AC: 13 AN: 242472 AF XY: 0.0000758

Gnomad AFR exome AF: 0.0000660

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: 0.00000915

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1458310 Hom.: 0 Cov.: 33 AF XY: 0.0000290 AC XY: 21 AN XY: 725154

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.000280 AC: 24 AN: 85590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52244

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5750

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110942

Other (OTH) AF: 0.00 AC: 0 AN: 60202

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74464

African (AFR) AF: 0.0000241 AC: 1 AN: 41548

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000803 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000825 AC: 10

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	-	-	Glycogen storage disease, type II (10)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MVP		1.0
MPC		0.54
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.95
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs536906561; hg19: chr17-78086728; COSMIC: COSV56412369; COSMIC: COSV56412369;