chr17-80110950-G-A

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1561G>A	p.Glu521Lys	missense_variant	Exon 11 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1561G>A	p.Glu521Lys	missense_variant	Exon 11 of 20	1	NM_000152.5	ENSP00000305692.3

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

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251268 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135856

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000324 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 31, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 521 of the GAA protein (p.Glu521Lys). This variant is present in population databases (rs121907937, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Pompe disease (PMID: 1898413, 17723315). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4022). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 1898413). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 20, 2014	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 03, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 15, 2024	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Glu521Lys variant in GAA has been reported in 11 individuals (including at least 3 Caucasian and 2 Indian individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 21605996, 19862843, 22704482, 1898413, 17723315, 17027861, 22676651, 25673129, 20033296, 20308911), and has been identified in 0.003% (1/30616) of South Asian chromosomes by gnomAD by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907937). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported likely pathogenic by Counsyl and pathogenic by OMIM in ClinVar (Variation ID: 4022). Another variant at this position, p.Glu521Val, has been reported as a VUS in association with disease in the literature (PMID: 25526786). In vitro functional studies, including transfection of COS cells and a Western Blot, provide some evidence that the p.Glu521Lys variant may impact protein processing and function (PMID: 1898413, 19862843). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with reported pathogenic variants in compound heterozygous individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu521Lys variant is pathogenic (PMID: 25673129, 17723315, 20033296). The phenotype of homozygous and heterozygous individuals with this variant is highly specific for Glycogen Storage Disease II based on GAA enzyme activity assays (PMID: 21605996, 25673129, 22676651, 20033296, 17723315, 1898413). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PM3, PS3, PM2, PP3, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion, Medical Genetics	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is in trans with NM_000152.5:c.1556T>C variant. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004022). The variant is in trans with the other variant. Different missense changes at the same codon (p.Glu521Gln, p.Glu521Val) have been reported to be associated with GAA related disorder (ClinVar ID: VCV000972760 / PMID: 18425781, 25526786). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2022	Variant summary: GAA c.1561G>A (p.Glu521Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251268 control chromosomes. c.1561G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) in the homozygous and compound heterozygous state (eg. Hermans_1991, Herzog_2012, Liu_2014, Montagnese_2016, etc). These data indicate that the variant is very likely to be associated with disease. The variant has been reported to have <10% enzyme activity in cell culture experiments (Hermans_1991, Flanagan_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	GAA: PM3:Strong, PM1, PM2, PM5, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 21, 2023	- -

Glycogen storage disease type II, infantile Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 16, 1991

- -

Computational scores

Source: dbNSFP v4.3

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;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;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;H
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121907937; hg19: chr17-78084749; COSMIC: COSV56408643; COSMIC: COSV56408643;