chr17-80108724-A-G

Variant names:

• chr17-80108724-A-G
• rs560575383
• NM_000152.5:c.1222A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2_Supporting PM3 PS3_Supporting PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1222A>G variant in GAA is predicted to result in the substitution of methionine by valine at amino acid 408 (p.Met408Val). Four patients have been reported with this variant; three with infantile onset Pompe disease and documented values showing GAA deficiency, at least two of them treated with enzyme replacement therapy (PMID:11738358, 26497565, 34995642). Another patient has later onset symptoms with reduction of urine Glc4 on enzyme replacement therapy (PMID:21687968) (PP4_Moderate). One individual is compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, c.1579del, confirmed in trans (PMID:34995642) (ClinVar Variation ID: 952947). Another patient is homozygous for the variant (PMID:26497565). Two patients are compound heterozygous for the variant and either c.1000G>A (p.Gly334Ser) (PMID:21687968) or c.1408_1410del (PMID:11738358); the allelic data for these two patients will be used in the classification of the other variant and is not included here to avoid circular logic (PM3). When expressed in COS-7 cells, this variant results in <2% wild type GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.637 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/111716 alleles) in the European, non-Finnish population. There is a ClinVar entry for this variant (Variation ID: 371235). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 26, 2020. Since then, the data for this variant have been re-evaluated. The classification of likely pathogenic was reapproved on May 6, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PS3_Supporting, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815236/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 2.56
• Publications: 14 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: Likely_pathogenic. The variant received 6 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.
• 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.1222A>G	p.Met408Val	missense	Exon 8 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1222A>G	p.Met408Val	missense	Exon 9 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1222A>G	p.Met408Val	missense	Exon 8 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.1222A>G	p.Met408Val	missense	Exon 8 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1222A>G	p.Met408Val	missense	Exon 9 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1222A>G	p.Met408Val	missense	Exon 8 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248202 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: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1460294 Hom.: 0 Cov.: 36 AF XY: 0.0000206 AC XY: 15 AN XY: 726438

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111862

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Glycogen storage disease, type II (6)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		2.6
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.63
MVP		0.99
MPC		0.52
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.79
gMVP		0.85
Mutation Taster		=36/64	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: rs560575383; hg19: chr17-78082523;