rs121907945

Positions:

• chr17-80107818-G-A
• chr17-80107818-G-C

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_000152.5:c.877G>A variant in GAA is a missense variant that is predicted to result in the substitution of glycine by arginine at amino acid 293 (p.Gly293Arg). Patients with a diagnosis of Pompe disease reported with this variant include five individuals with documented laboratory values showing deficient GAA activity meeting the specifications of the ClinGen LSD VCEP (PMIDs: 23566438, 24590251, 26497565), one of whom also has features reported that are consistent with infantile onset Pompe disease (PMID:31510962) and additional patients reported to be on enzyme replacement therapy but without documentation of residual GAA activity (PMID:18607768, 21605996) (PP4_Moderate). At least 6 patients are compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including c.-32-13T>G (PMIDs: 18607768, 21605996, 23566438, 24590251, 25455803, 29181627, 31710733), c.2481+102_2646+31del (PMID:18429042) and c.716del (p.Leu239fsTer28) (PMID:14695532), and at least two individuals are homozygous for the variant (PMIDs: 31510962, 26497565) (2 x 0.5 points) (PM3_Strong). In addition, two patients are compound heterozygous for the variant and either c.719C>T (p.Phe240Ser; note that reference sequence has a T at position 719) (PMID:25455803) or c.710C>T (p.Ala237Val) (PMIDs: 15668445, 17573812, 17643989. The allelic data from these patients will be used in the classification of p.Phe240Ser and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00006 (2/35062 alleles) in the Latino / Admixed American 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 results in <2% residual GAA activity in medium and cells (PMIDs 14695532, 19862843). No GAA protein was observed on Western blot of COS cells expressing the variant (PMID 14695532) (PS3_Moderate). The computational predictor REVEL gives a score of 0.931 which is above the threshold of 0.7, evidence that correlates with impact to GAA function, and SpliceAI predicts the creation of a cryptic splice site 2 nucleotides downstream from the variant (PP3). There is a ClinVar entry for this variant (Variation ID: 4036; 2 star review status) with 6 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. )Classification approved by the ClinGen LSD VCEP on Nov. 2, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116622/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 7.93

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.877G>A	p.Gly293Arg	missense_variant	5/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.877G>A	p.Gly293Arg	missense_variant	5/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152158 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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000163 AC: 4 AN: 245436 Hom.: 0 AF XY: 0.0000225 AC XY: 3 AN XY: 133576

Gnomad AFR exome AF: 0.0000637

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000481

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459656 Hom.: 0 Cov.: 56 AF XY: 0.00000689 AC XY: 5 AN XY: 726162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

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: 0.0000263 AC: 4 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74324

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: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.00000825 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

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	Oct 23, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 293 of the GAA protein (p.Gly293Arg). This variant is present in population databases (rs121907945, gnomAD 0.006%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 14695532, 15668445, 17573812, 18607768, 22676651, 24590251, 27344650, 29122469, 29181627). ClinVar contains an entry for this variant (Variation ID: 4036). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.Gly293Arg variant in GAA has been reported in 8 individuals (including 2 Germans, 2 from the UK, 1 Italian, and 1 Afghan individuals) with Glycogen Storage Disease II (PMID: 14695532, 18429042, 23566438, 15668445, 18607768, 26497565), and has also been reported pathogenic by Invitae, EGL Genetic Diagnostics, OMIM, and Klinikum rechts der Isar in ClinVar (Variation ID: 4036). This variant has been identified in 0.006% (2/35062) of Latino chromosomes, 0.004% (1/24260) of European (non-Finnish) chromosomes, and 0.004% (1/24388) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907945). 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.Gly293Arg variant may impact GAA activity and levels (PMID: 14695532, 19862843). 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 reported pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly293Arg variant is pathogenic (PMID: 26497565, 23566438). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low levels of GAA activity in leukocytes, muscle, or lymphocytes (PMID: PMID: 26497565, 23566438). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies with COS cells transfected with the variant and multiple occurrences with reported pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3, PP4, PM2, PP3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jun 22, 2023	The homozygous mis-sense variant c.877G>A (p.Gly293Arg) has been identified in a proband with cardiomegaly, cardiomyopathy and respiratory distress. This variant has been found 0.0018%gnomAD (aggregated). This has been previously reported PMID: 31342611 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2019	Variant summary: GAA c.877G>A (p.Gly293Arg) results in a non-conservative amino acid change located in the N-terminal domain (IPR025887) of 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 1.6e-05 in 245436 control chromosomes (gnomAD). c.877G>A has been reported in the literature in several compound heterozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Hermans_2004, Muller-Felber_2007, Angelini_2012, Herzog_2012). These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated a less 10% of normal enzyme activity for the variant protein (Hermans_2004, Flanagan_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of these laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 16, 2017	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Nov 02, 2022	The NM_000152.5:c.877G>A variant in GAA is a missense variant that is predicted to result in the substitution of glycine by arginine at amino acid 293 (p.Gly293Arg). Patients with a diagnosis of Pompe disease reported with this variant include five individuals with documented laboratory values showing deficient GAA activity meeting the specifications of the ClinGen LSD VCEP (PMIDs: 23566438, 24590251, 26497565), one of whom also has features reported that are consistent with infantile onset Pompe disease (PMID: 31510962) and additional patients reported to be on enzyme replacement therapy but without documentation of residual GAA activity (PMID: 18607768, 21605996) (PP4_Moderate). At least 6 patients are compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP including c.-32-13T>G (PMIDs: 18607768, 21605996, 23566438, 24590251, 25455803, 29181627, 31710733), c.2481+102_2646+31del (PMID: 18429042) and c.716del (p.Leu239fsTer28) (PMID: 14695532), and at least two individuals are homozygous for the variant (PMIDs: 31510962, 26497565) (2 x 0.5 points) (PM3_Strong). In addition, two patients are compound heterozygous for the variant and either c.719C>T (p.Phe240Ser; note that reference sequence has a T at position 719) (PMID: 25455803) or c.710C>T (p.Ala237Val) (PMIDs: 15668445, 17573812, 17643989. The allelic data from these patients will be used in the classification of p.Phe240Ser and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00006 (2/35062 alleles) in the Latino / Admixed American 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 results in <2% residual GAA activity in medium and cells (PMIDs 14695532, 19862843). No GAA protein was observed on Western blot of COS cells expressing the variant (PMID 14695532) (PS3_Moderate). The computational predictor REVEL gives a score of 0.931 which is above the threshold of 0.7, evidence that correlates with impact to GAA function, and SpliceAI predicts the creation of a cryptic splice site 2 nucleotides downstream from the variant (PP3). There is a ClinVar entry for this variant (Variation ID: 4036; 2 star review status) with 6 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. )Classification approved by the ClinGen LSD VCEP on Nov. 2, 2022) -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2023	Published functional studies demonstrate a damaging effect on protein function (Hermans et al., 2004; Flanagan et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function and on splicing; Located in the N-terminal -sandwich domain (Kroos et al., 2012; Sugawara et al., 2009); This variant is associated with the following publications: (PMID: 34530085, 31254424, 30275481, 24590251, 29181627, 27344650, 14695532, 18429042, 15668445, 31606152, 22676651, 31510962, 29122469, 18607768, 17573812, 19862843, 22253258, 19343043) -

GLYCOGEN STORAGE DISEASE II, ADULT FORM Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 25, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	36
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.94		Gain of methylation at G293 (P = 0.0461);Gain of methylation at G293 (P = 0.0461);
MVP		1.0
MPC		0.59
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.98
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.75		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121907945; hg19: chr17-78081617;