rs991082382

Positions:

• chr17-80112081-G-A
• chr17-80112081-G-C
• chr17-80112081-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_Moderate PP3 PS3_Moderate PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000152.:c.1735G>A variant in GAA is a missense variant predicted to result in the substitution of glutamate by lysine at amino acid 579 (p.Glu579Lys). Five patients with a diagnosis of Pompe disease and the variant have been reported, three with documented laboratory values showing deficiency of GAA activity (PMID:21676566, 23601496, 29124014, 34357340), one with reported features consistent with infantile-onset Pompe disease (PMID:24269976), and another reported to have Pompe disease (PMID:14695532) (PP4_Moderate). Four of these patients are compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, all phase unknown, including c.-32-13T>G (PMID:34357340) (0.5 points), c.525delT (PMID:14695532) (0.5 points), c.2237G>A (p.Trp746Ter) (PMID:24269976) (0.5 points), and c.655G>A (p.Gly219Arg) (PMIDs: 23601496, 31086307,31193175) (0.5 points). Total 2 points (PM3_Strong). Another patient is compound heterozygous for the variant and c.1857C>G (p.Ser619Arg) (PMIDs: 21676566, 29124014) The allelic data from this patient will be used in the classification of p.Ser619Arg and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/129092) in the European Non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had <5% GAA activity in cells and <2% in medium, evidence of abnormal synthesis and processing on Western blot, and did not localize to the lysosomes (PMID:14695532, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.878 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: 495664). In summary this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the Clingen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting.(Classification approved by the ClinGen LSD VCEP on December 6, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA294895841/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 7.45

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 10 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.1735G>A	p.Glu579Lys	missense_variant	12/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1735G>A	p.Glu579Lys	missense_variant	12/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152208 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251264 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135858

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461600 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 06, 2023	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Glu579Lys variant in GAA has been reported in 4 individuals (including 1 Australian, 1 Japanese, 1 Chinese, and 1 Caucasian individuals) with Glycogen Storage Disease II (PMID: 21676566, 14695532, 24269976, 23601496), and has also been reported pathogenic by Integrated Genetics in ClinVar (Variation ID: 495664). This variant has been identified in 0.002% (2/129092) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs991082382). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Glu579Lys variant may impact GAA processing and activity (PMID: 14695532). 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 a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Glu579Lys variant is pathogenic (PMID: 23601496). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with reduced GAA activity detected in their skin fibroblasts or muscle (PMID: 23601496, 21676566). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Supporting, PS3, PM2, PP3, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 22, 2016	Variant summary: The GAA c.1735G>A (p.Glu579Lys) variant located in the glycoside hydrolase superfamily domain (via InterPro) causes a missense change involving a conserved nucleotide with 4/5 in silico tools predicting a "damaging" outcome, which is supported by multiple functional studies. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and multiple publications cite the variant in compound heterozygote affected individuals. Therefore, the variant of interest has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 27, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 24, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 579 of the GAA protein (p.Glu579Lys). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with Pompe disease (PMID: 14695532, 21676566, 24269976, 29124014, 31342611). ClinVar contains an entry for this variant (Variation ID: 495664). 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: 14695532, 19862843). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 06, 2022	The NM_000152.:c.1735G>A variant in GAA is a missense variant predicted to result in the substitution of glutamate by lysine at amino acid 579 (p.Glu579Lys). Five patients with a diagnosis of Pompe disease and the variant have been reported, three with documented laboratory values showing deficiency of GAA activity (PMID: 21676566, 23601496, 29124014, 34357340), one with reported features consistent with infantile-onset Pompe disease (PMID: 24269976), and another reported to have Pompe disease (PMID: 14695532) (PP4_Moderate). Four of these patients are compound heterozygous for the variant and a variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, all phase unknown, including c.-32-13T>G (PMID: 34357340) (0.5 points), c.525delT (PMID: 14695532) (0.5 points), c.2237G>A (p.Trp746Ter) (PMID: 24269976) (0.5 points), and c.655G>A (p.Gly219Arg) (PMIDs: 23601496, 31086307,31193175) (0.5 points). Total 2 points (PM3_Strong). Another patient is compound heterozygous for the variant and c.1857C>G (p.Ser619Arg) (PMIDs: 21676566, 29124014) The allelic data from this patient will be used in the classification of p.Ser619Arg and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002 (2/129092) in the European Non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had <5% GAA activity in cells and <2% in medium, evidence of abnormal synthesis and processing on Western blot, and did not localize to the lysosomes (PMID: 14695532, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.878 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: 495664). In summary this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the Clingen Lysosomal Storage Disorders VCEP (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LSD VCEP on December 6, 2022) -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 11, 2022	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 29, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 28, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		0.99	D;D
Vest4		0.80
MVP		1.0
MPC		0.54
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs991082382; hg19: chr17-78085880;