17-80110953-C-G

Position:

• chr17-80110953-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PP4_Moderate PM3_Strong PM5_Supporting PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1564C>G variant in GAA is a missense variant predicted to cause substitution of proline by alanine at amino acid 522 (p.Pro522Ala). This variant has been detected in at least 7 unrelated patients reported to have Pompe disease including four individuals with reported laboratory values demonstrating deficient GAA activity (PMID:26800218, 33301762, 34072668, Duke University), and three for whom GAA activity was not reported (PMID:18429042, 37087815) (PP4_Moderate). Of those individuals, 6 were compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LD VCEP: c.784G>A (p.Glu262Lys) (ClinVar Variation ID: 188806, SCV002032128.1) (PMID:18429042), c.1933G>A (p.Asp645Asn) (ClinVar Variation ID: 188728, SCV001371736.1) (PMID:18429042), c.1465G>A (p.Asp489Asn) (ClinVar Variation ID: 92465, SCV003852732.1) (PMID:34072668), and c.-32-13T>G (ClinVar Variation ID: 4027) (PMID:26800218, 37087815, Clinical Diagnostic Laboratory; at least 3 unrelated patients). The phase is not confirmed for any of these individuals. One individual was homozygous for this variant (PMID:33301762) (PM3_Strong). Another missense variant, c.1564C>T, p.Pro522Ser (ClinVar Variation ID: 972746) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in Ad5-SV40 immortalized human GAA-deficient fibroblast cell line resulted in 0% wild type GAA activity when measured using fluorogenic substrate 4-methylumbelliferyl-α-D glucopyranoside. This was further supported via Western blot analysis demonstrating deficient GAA protein expression (PMID:18429042) (PS3_Supporting). The computational predictor REVEL gives a score of 0.883 which is above the threshold predicting a damaging (>0.7) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 371277). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PM2_Supporting, PM5_Supporting PS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041893/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA ENST00000302262.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 6.02

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.
• PM5: 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.1564C>G	p.Pro522Ala	missense_variant	11/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1564C>G	p.Pro522Ala	missense_variant	11/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461636 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727104

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2023	ClinVar contains an entry for this variant (Variation ID: 371277). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GAA function (PMID: 18429042). 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. This missense change has been observed in individual(s) with Pompe disease (PMID: 17643989, 18429042, 26800218, 29422078). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 522 of the GAA protein (p.Pro522Ala). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 12, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Mar 19, 2024	The NM_000152.5:c.1564C>G variant in GAA is a missense variant predicted to cause substitution of proline by alanine at amino acid 522 (p.Pro522Ala). This variant has been detected in at least 7 unrelated patients reported to have Pompe disease including four individuals with reported laboratory values demonstrating deficient GAA activity (PMID: 26800218, 33301762, 34072668, Duke University), and three for whom GAA activity was not reported (PMID: 18429042, 37087815) (PP4_Moderate). Of those individuals, 6 were compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LD VCEP: c.784G>A (p.Glu262Lys) (ClinVar Variation ID: 188806, SCV002032128.1) (PMID: 18429042), c.1933G>A (p.Asp645Asn) (ClinVar Variation ID: 188728, SCV001371736.1) (PMID: 18429042), c.1465G>A (p.Asp489Asn) (ClinVar Variation ID: 92465, SCV003852732.1) (PMID: 34072668), and c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 26800218, 37087815, Clinical Diagnostic Laboratory; at least 3 unrelated patients). The phase is not confirmed for any of these individuals. One individual was homozygous for this variant (PMID: 33301762) (PM3_Strong). Another missense variant, c.1564C>T, p.Pro522Ser (ClinVar Variation ID: 972746) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in Ad5-SV40 immortalized human GAA-deficient fibroblast cell line resulted in 0% wild type GAA activity when measured using fluorogenic substrate 4-methylumbelliferyl-α-D glucopyranoside. This was further supported via Western blot analysis demonstrating deficient GAA protein expression (PMID: 18429042) (PS3_Supporting). The computational predictor REVEL gives a score of 0.883 which is above the threshold predicting a damaging (>0.7) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 371277). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PM2_Supporting, PM5_Supporting PS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 17, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 23, 2020	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 19, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.025	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.97		Loss of disorder (P = 0.0763);Loss of disorder (P = 0.0763);
MVP		1.0
MPC		0.53
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.86
gMVP		0.92

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: rs892129065; hg19: chr17-78084752;