17-80110730-T-C

Position:

• chr17-80110730-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_Supporting PM3_Strong PS3_Supporting PP4_Moderate PM1 PP3

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1441T>C variant in GAA is predicted to result in the missense substitution of tryptophan by arginine at amino acid 481 (p.Trp481Arg). The variant has been reported in at least 6 individuals with Pompe disease in compound heterozygosity with another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. It was confirmed in trans with c.1326+1G>A (PMIDs: 10189220, 9862843), and was found in unconfirmed phase with c.-32-13T>G (PMID:14695532, 18757064, 22676651, 27189384, 29556838, 34357340); c.2560C>T (p.Arg854Ter) (PMIDs: 31086307, 35787971), c.1979G>A (p.Arg660His) (PMID:31086307), and c.2481+102_c.2646+31del (PMID:26497565, 28657663). Another patient is compound heterozygous for the variant and c.1556T>C (p.Met519Thr) (PMID:31086307); the allelic data from this patient will be used in the assessment of the other variant and is not included here to avoid circular logic (PM3_Strong). This variant has been reported in individuals with specific phenotypic features of Pompe disease including documented laboratory values revealing GAA deficiency, individuals on enzyme replacement therapy, patients with documented symptoms of infantile onset Pompe disease, and elevated urine Hex4 (PMID:26497565, 28657663, 31086307, 34357340) (PP4_Moderate). Trp481 is a residue that crystallography studies have shown to be important in the architecture of the active site and substrate binding of GAA; this residues has, therefore, has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID:29061980) (PM1). In two independent studies, expression of the variant in COS cells results in <2% GAA activity compared to normal, but also a significant amount of mature GAA protein, suggesting that the variant impacts catalysis rather than protein production or stability (PMID:14695532, 19862843). The computational predictor REVEL gives a score of 0.967 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: ). 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 Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PM1, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting, (Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 1, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274247/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 7.52

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 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.1441T>C	p.Trp481Arg	missense_variant	10/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1441T>C	p.Trp481Arg	missense_variant	10/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250876 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135762

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: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000794 AC: 116 AN: 1461552 Hom.: 0 Cov.: 37 AF XY: 0.0000715 AC XY: 52 AN XY: 727106

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: 0.000103

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

Gnomad4 AFR AF: 0.0000724

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Feb 09, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 481 of the GAA protein (p.Trp481Arg). This variant is present in population databases (rs772883420, gnomAD 0.008%). This missense change has been observed in individual(s) with Pompe disease (PMID: 18757064; 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: 189007). 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, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Trp481Arg variant in GAA has been reported in 6 individuals (including 1 African American and 1 German individuals) with Glycogen Storage Disease II (PMID: 27189384, 18757064, 10189220, 19862843, 26497565, 22676651, 14695532, 28657663), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae and Integrated Genetics in ClinVar (Variation ID: 189007). This variant has been identified in 0.008% (2/24904) of African chromosomes and 0.003% (4/128730) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs772883420). 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.Trp481Arg variant may impact ligand binding and GAA activity but not GAA levels (PMID: 19862843, 14695532, 15501829). 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 pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp481Arg variant is pathogenic (PMID: 26497565, 22676651, 27189384, 28657663). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on very low GAA activity in assays with relevant tissue (PMID: 26497565, 22676651, 27189384, 28657663). In summary, this variant meets criteria to be classified as pathogenic for p.Trp481Arg in an autosomal recessive manner based on in vitro functional evidence and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2018	Variant summary: GAA c.1441T>C (p.Trp481Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 276888 control chromosomes. c.1441T>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), with reported severely deficient GAA enzyme activity (Tsai_2017, Hermans_2004, Herzog_2012, Raben_1998, van Capelle2016). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Oct 01, 2023	The NM_000152.5:c.1441T>C variant in GAA is predicted to result in the missense substitution of tryptophan by arginine at amino acid 481 (p.Trp481Arg). The variant has been reported in at least 6 individuals with Pompe disease in compound heterozygosity with another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. It was confirmed in trans with c.1326+1G>A (PMIDs: 10189220, 9862843), and was found in unconfirmed phase with c.-32-13T>G (PMID: 14695532, 18757064, 22676651, 27189384, 29556838, 34357340); c.2560C>T (p.Arg854Ter) (PMIDs: 31086307, 35787971), c.1979G>A (p.Arg660His) (PMID: 31086307), and c.2481+102_c.2646+31del (PMID: 26497565, 28657663). Another patient is compound heterozygous for the variant and c.1556T>C (p.Met519Thr) (PMID: 31086307); the allelic data from this patient will be used in the assessment of the other variant and is not included here to avoid circular logic (PM3_Strong). This variant has been reported in individuals with specific phenotypic features of Pompe disease including documented laboratory values revealing GAA deficiency, individuals on enzyme replacement therapy, patients with documented symptoms of infantile onset Pompe disease, and elevated urine Hex4 (PMID: 26497565, 28657663, 31086307, 34357340) (PP4_Moderate). Trp481 is a residue that crystallography studies have shown to be important in the architecture of the active site and substrate binding of GAA; this residues has, therefore, has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID: 29061980) (PM1). In two independent studies, expression of the variant in COS cells results in <2% GAA activity compared to normal, but also a significant amount of mature GAA protein, suggesting that the variant impacts catalysis rather than protein production or stability (PMID: 14695532, 19862843). The computational predictor REVEL gives a score of 0.967 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: ). 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 Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PM1, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting, (Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 1, 2023) -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 02, 2024	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 12, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31254424, 19862843, 21228398, 28657663, 22676651, 18757064, 15501829, 16580018, 31086307, 10189220, 14695532, 26497565, 27189384, 33202836, 29556838, 27535533, 22253258, 19343043) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 04, 2024	PP3_strong, PP4_moderate, PM3_strong, PS3_supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-13	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.94		Gain of methylation at W481 (P = 0.0094);Gain of methylation at W481 (P = 0.0094);
MVP		1.0
MPC		0.72
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs772883420; hg19: chr17-78084529;