17-80112619-C-A

Position:

• chr17-80112619-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2_Supporting PS3_Moderate PP4_Moderate PM3 PP3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1796C>A variant in GAA is a missense variant predicted to cause substitution of serine by tyramine at amino acid 599 (p.Ser599Tyr). At least 4 probands have been reported with clinical symptoms consistent with Pompe, typically late onset of symptoms, and documentation of reduced enzyme activity in the affected range (PMID:37087815 and/or on enzyme replacement therapy (PMID:29122469, 29803406, 31710733). Additional patients have symptoms consistent with Pompe disease but no details were available on GAA activity (PMID:32419263). At least 4 individuals are compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.-32-13T>G (at least 2 patients) (PMID:29122469, 31710733, 32419263, 37087815) (max 2 x 0.5 points = 1 point), and c.655G>A (p.Gly219Arg) (PMID:18429042) (0.5 points). Another individuals is compound heterozygous for the variant and c.364A>G (p.Met122Val); phase unknown (PMID:29803406). The allelic data for the proband will be used in the assessment of p.Met122Val and is not included here to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v2.1.0 is 0.00002683 (3/111834; no homozygotes) and in gnomAD v4.1.0 it is 0.000005932 (7/1179950; no homozygotes) in the European (non-Finnish) population, which is lower than the ClinGen LD VCEP threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 0% wild type GAA activity and evidence of abnormal GAA synthesis and processing leading the variant to be described as Class A (“very severe”). An additional study demonstrated 0% GAA activity in Ad5-SV40 fibroblast cells and abnormal Western blot results, indicating that this variant may impact protein function (PMIDs 18425781, 18429042)(PS3_Moderate). The computational predictor REVEL gives a score of 0.974 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 551558). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2): PS3_Moderate, PM3, PP3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 22, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815479/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 7.75

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 (HGNC:):

ACMG classification

Verdict is Likely_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/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.1796C>A	p.Ser599Tyr	missense_variant	13/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1796C>A	p.Ser599Tyr	missense_variant	13/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248524 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135220

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460674 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726674

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000365 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:6 Uncertain:1

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ser599Tyr variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 29122469, 18429042, 18425781) and has been identified in 0.003% (3/111834) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753505203). 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 in ClinVar as a VUS by Counsyl and Invitae (VariationID: 551558). In vitro function studies using COS-7 cells and fibroblasts transfected with the variant provide some evidence that the p.Ser599Tyr variant causes null enzyme activity (PMID: 18429042, 18425781). 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. In addition, this variant was reported in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027, PMID: 29122469) and pathogenic variant p.Gly219Arg (VariationID: 189065, PMID: 18429042) and in individuals with glycogen storage disease II. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3 (Richards 2015). -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Nov 22, 2024	The NM_000152.5:c.1796C>A variant in GAA is a missense variant predicted to cause substitution of serine by tyramine at amino acid 599 (p.Ser599Tyr). At least 4 probands have been reported with clinical symptoms consistent with Pompe, typically late onset of symptoms, and documentation of reduced enzyme activity in the affected range (PMID: 37087815 and/or on enzyme replacement therapy (PMID: 29122469, 29803406, 31710733). Additional patients have symptoms consistent with Pompe disease but no details were available on GAA activity (PMID: 32419263). At least 4 individuals are compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.-32-13T>G (at least 2 patients) (PMID: 29122469, 31710733, 32419263, 37087815) (max 2 x 0.5 points = 1 point), and c.655G>A (p.Gly219Arg) (PMID: 18429042) (0.5 points). Another individuals is compound heterozygous for the variant and c.364A>G (p.Met122Val); phase unknown (PMID: 29803406). The allelic data for the proband will be used in the assessment of p.Met122Val and is not included here to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v2.1.0 is 0.00002683 (3/111834; no homozygotes) and in gnomAD v4.1.0 it is 0.000005932 (7/1179950; no homozygotes) in the European (non-Finnish) population, which is lower than the ClinGen LD VCEP threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 0% wild type GAA activity and evidence of abnormal GAA synthesis and processing leading the variant to be described as Class A (“very severe”). An additional study demonstrated 0% GAA activity in Ad5-SV40 fibroblast cells and abnormal Western blot results, indicating that this variant may impact protein function (PMIDs 18425781, 18429042)(PS3_Moderate). The computational predictor REVEL gives a score of 0.974 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 551558). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2): PS3_Moderate, PM3, PP3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 22, 2024). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 599 of the GAA protein (p.Ser599Tyr). This variant is present in population databases (rs753505203, gnomAD 0.003%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy and/or Pompe disease (PMID: 18429042, 29122469, 31342611; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 551558). 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: 18429042). This variant disrupts the p.Ser599 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 26253708), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 15, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 19, 2023	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jan 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;H
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.94		Loss of glycosylation at S599 (P = 0.0372);Loss of glycosylation at S599 (P = 0.0372);
MVP		1.0
MPC		0.62
ClinPred		0.98	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs753505203; hg19: chr17-78086418;