rs121907937

Variant names:

• chr17-80110950-G-A
• rs121907937
• NM_000152.5:c.1561G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80110950-G-A
• chr17-80110950-G-C

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PM2_Supporting PS3_Moderate PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1561G>A variant in GAA is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 521 (p.Glu521Lys). This substitution of a negatively charged, polar amino acid with a neutral, non-polar amino acid is predicted to functionally impact the GAA precursor protein (PMID:1898413). This variant was first reported in homozygosity in a case report of siblings with IOPD and no detectable GAA activity in fibroblasts (PMID:1898413), meeting criteria for PP4_moderate. This variant has been detected in at least four additional individuals with IOPD. Of those individuals, two were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMIDs: 17723315, 37542277) and two were homozygous for the variant (PMIDs: 19862843,33301762). This variant has also been reported in at least nine individuals with LOPD. Of those, six were compound heterozygous for the common IVS splice site pathogenic variant c.-32-13T>G (PMIDs: 22676651, 20308911, 2270448, 20033296, 25673129, 30312517,34852371 and 39045638), and one was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID:21605996 and 22676651) (PM3_Very Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003334 (2/59992 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In the first report of this variant, transient expression in COS cells was performed and revealed no detectable activity, and immunocytochemistry results suggested the mutant precursor is not transported to the lysosome (PMID:1898413). Subsequent expression studies in COS cells revealed <2% wild type GAA activity, indicating that this variant may impact protein function (PMID:19862843). Thus, PS3_Supporting can be applied. The computational predictor REVEL gives a score of 0.932 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense change at the same amino acid position (p.Glu521Gln) has been reported in IOPD (PMID:22658377, 19588081), but this variant has not been reviewed by the ClinGen Lysosomal Diseases Variant Curation Expert panel and thus PM5 will not be applied. There is a ClinVar entry for this variant (Variation ID: 4022, 2-star review status) with 8 submitters classifying the variant as pathogenic (7 submitters) or likely pathogenic (1 submitters). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM3_Very Strong, PP4_moderate, PM2_supporting, PP3, PS3_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 3, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116593/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 9.80
• Publications: 16 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: Pathogenic. The variant received 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.1561G>A	p.Glu521Lys	missense	Exon 11 of 20	NP_000143.2
	GAA	NM_001079803.3		c.1561G>A	p.Glu521Lys	missense	Exon 12 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.1561G>A	p.Glu521Lys	missense	Exon 11 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1561G>A	p.Glu521Lys	missense	Exon 11 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.1561G>A	p.Glu521Lys	missense	Exon 12 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.1561G>A	p.Glu521Lys	missense	Exon 11 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251268 AF XY: 0.00000736

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: 0.00000342 AC: 5 AN: 1461630 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 727108

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000217 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Glycogen storage disease, type II (9)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		1.0
MPC		0.57
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		1.0
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121907937; hg19: chr17-78084749; COSMIC: COSV56408643; COSMIC: COSV56408643;