rs398123172

Positions:

• chr17-80113282-G-A
• chr17-80113282-G-C
• chr17-80113282-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5 PS3_Supporting PP4_Moderate PP3 PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2105G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 702 (p.Arg702His). At least 3 unrelated patients were noted to have deficient GAA activity but results were not provided (PMID:26310554, 30897595, 28394184). Two patients are described as having IOPD with clinical symptoms consistent with IOPD reported in one (PMID:26310554). One patient is described as having juvenile-onset Pompe disease with deficient GAA (value not provided) (PMID:18211760). Another patient is reported to have deficient GAA and late-onset Pompe disease (PMID:30897595) (PP4_Moderate). At least one patient is described as having this variant in trans with a variant classified as likely pathogenic by the ClinGen Lysosomal Diseases (LD) VCEP (c.796C>T, p.Pro266Ser; ClinVar Variation ID Variation ID: 556117; SCV002540664.1) (PMID:18211760). At least two patients have been reported with this variant in compound heterozygosity with another variant that has been classified as pathogenic by the ClinGen LD VCEP (c.2297A>C, p.Tyr766Ser, ClinVar Variation ID: Variation ID: 420102, SCV002540647.1, and c.2238G>C, p.Trp746Cys, ClinVar Variation ID: Variation ID: 265160, SCV002032122.1), phase unconfirmed for both (PMID:28394184 and 30897595) (PM3_Strong). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.985, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Expression of the variant in COS-7 cells resulted in 5% wild type GAA activity in medium and 13% residual activity in cells with evidence of abnormal synthesizing and processing (PMID:18425781) leading the variant to be described as Class D “potentially mild” indicating that this variant may impact protein function (PS3_supporting). Another missense variant (c.2105G>T, p.Arg702Leu) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP (ClinVar Variation ID: Variation ID: 92472)(PM5). There is a ClinVar entry for this variant (Variation ID: 426278). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_strong, PM5, PP4_moderate, PM2_supporting, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815610/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12 U:2
• Conservation: PhyloP100: 9.74

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.
• 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.2105G>A	p.Arg702His	missense_variant	15/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2105G>A	p.Arg702His	missense_variant	15/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152148 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

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: 0.0000539 AC: 12 AN: 222484 Hom.: 0 AF XY: 0.0000582 AC XY: 7 AN XY: 120216

Gnomad AFR exome AF: 0.0000733

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000730

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000249 AC: 36 AN: 1448060 Hom.: 0 Cov.: 35 AF XY: 0.0000236 AC XY: 17 AN XY: 719012

Gnomad4 AFR exome AF: 0.0000902

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000478

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000217

Gnomad4 OTH exome AF: 0.0000501

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152148 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74314

Gnomad4 AFR AF: 0.0000483

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: 0.0000450 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 702 of the GAA protein (p.Arg702His). This variant is present in population databases (rs398123172, gnomAD 0.009%). This missense change has been observed in individuals with Pompe disease (PMID: 18211760, 26310554, 28394184). ClinVar contains an entry for this variant (Variation ID: 426278). 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: 18425781). This variant disrupts the p.Arg702 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14972326, 22252923, 24158270, 27344650, 29122469). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2017	Variant summary: The GAA c.2105G>A (p.Arg702His) variant involves the alteration of a conserved nucleotide located in the Glycoside hydrolase superfamily domain of the protein (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 13/248554 control chromosomes in genomAD at a frequency of 0.0000523, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). This variant has been reported in multiple Pompe pts. Functional study showed deficient enzyme activity, and variant was classified as a mild pathogenic mutation (Kroos_2008) . In addition, one other clinical diagnostic laboratory classified this variant as pathogenic. Variant involving the same codon Arg702Cys has been reported in affected individuals suggesting functional importance of this location. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 23, 2021	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Mar 05, 2024	The NM_000152.5:c.2105G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 702 (p.Arg702His). At least 3 unrelated patients were noted to have deficient GAA activity but results were not provided (PMID: 26310554, 30897595, 28394184). Two patients are described as having IOPD with clinical symptoms consistent with IOPD reported in one (PMID: 26310554). One patient is described as having juvenile-onset Pompe disease with deficient GAA (value not provided) (PMID: 18211760). Another patient is reported to have deficient GAA and late-onset Pompe disease (PMID: 30897595) (PP4_Moderate). At least one patient is described as having this variant in trans with a variant classified as likely pathogenic by the ClinGen Lysosomal Diseases (LD) VCEP (c.796C>T, p.Pro266Ser; ClinVar Variation ID Variation ID: 556117; SCV002540664.1) (PMID: 18211760). At least two patients have been reported with this variant in compound heterozygosity with another variant that has been classified as pathogenic by the ClinGen LD VCEP (c.2297A>C, p.Tyr766Ser, ClinVar Variation ID: Variation ID: 420102, SCV002540647.1, and c.2238G>C, p.Trp746Cys, ClinVar Variation ID: Variation ID: 265160, SCV002032122.1), phase unconfirmed for both (PMID: 28394184 and 30897595) (PM3_Strong). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.985, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Expression of the variant in COS-7 cells resulted in 5% wild type GAA activity in medium and 13% residual activity in cells with evidence of abnormal synthesizing and processing (PMID: 18425781) leading the variant to be described as Class D “potentially mild” indicating that this variant may impact protein function (PS3_supporting). Another missense variant (c.2105G>T, p.Arg702Leu) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen LD VCEP (ClinVar Variation ID: Variation ID: 92472)(PM5). There is a ClinVar entry for this variant (Variation ID: 426278). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_strong, PM5, PP4_moderate, PM2_supporting, PP3, PS3_supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Arg702His variant in GAA has been reported in 4 individuals (3 Chinese and 1 Turkish/Dutch individuals) with Glycogen Storage Disease II (PMID: 28394184, 18211760, 26310554, 18425781). This variant has also been reported pathogenic by GeneDx, Integrated Genetics, and Invitae and likely pathogenic by EGL Genetic Diagnostics and Counsyl in ClinVar (Variation ID: 426278). This variant has been identified in 0.009% (2/22334) of African chromosomes, 0.008% (9/114642) of European (non-Finnish) chromosomes, and 0.007304% (2/27382) South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123172). 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.Arg702His variant may impact enzyme levels and activity (PMID: 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. This variant was reported in combination with a likely pathogenic variant and in individuals with Glycogen Storage Disease II (PMID: 28394184, 18211760). Two additional variants at the the same position, p.Arg702Cys and p.Arg702Leu, have been reported likely pathogenic or pathogenic in association with disease in the literature and ClinVar or curated by our study, supporting that a change at this position may not be tolerated (PMID: 28394184, 27344650, 24158270, 14972326; Variation ID: 92472). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PS3_Moderate, PM2, PP3 (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_000152.3(GAA):c.2105G>A(R702H) is a missense variant classified as likely pathogenic in the context of Pompe disease. R702H has been observed in cases with relevant disease (PMID: 18425781, 18211760, 28394184, 26310554, 27344650, 30897595, 29325298). Functional assessments of this variant are available in the literature (PMID: 18425781). R702H has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, NM_000152.3(GAA):c.2105G>A(R702H) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

not provided Pathogenic:3 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2024	Published functional studies demonstrate a damaging effect leading to significantly reduced but not absent enzyme activity compared to wild-type (PMID: 18425781); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26310554, 31254424, 30275481, 18425781, 18211760, 27344650, 29325298, 31342611, 30526868, 32064362, 22253258, 19343043, 34426522, 28394184, 38186848, 30897595, 39010129) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2017	- -

GAA-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

The GAA c.2105G>A variant is predicted to result in the amino acid substitution p.Arg702His. This variant has been reported with a second GAA variant in individuals with glycogen storage disease II (see, for example, Kroos et al. 2008. PubMed ID: 18425781; Chen X et al 2017. PubMed ID: 28394184; Lyu et al. 2019. PubMed ID: 30897595). In vitro experimental studies suggest this variant has a mild impact on protein function (Kroos et al. 2008. PubMed ID: 18425781). Alternative amino acid changes at this position (p.Arg702Cys, p.Arg702Leu) have also been reported in individuals with glycogen storage disease II (Montalvo et al. 2004. PubMed ID: 14972326; Bali et al. 2012. PubMed ID: 22252923). This variant is reported in 0.0090% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78087081-G-A). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		1.0
MutPred		0.97		Gain of methylation at K697 (P = 0.0379);Gain of methylation at K697 (P = 0.0379);
MVP		1.0
MPC		0.60
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.97
gMVP		0.97

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: rs398123172; hg19: chr17-78087081;