rs770590394

Positions:

• chr17-80110736-G-A

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.1447G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 483 (p.Gly483Arg). At least 7 individuals with this variant have been reported to have Pompe disease. Of these individuals, 3 were compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, with unknown phase, including c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (0.5 points, PMID:30214072, 33073009), c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (0.5 points, PMID:33073009), and c.32-13T>G (ClinVar Variation ID: 4027) (0.5 points, PMID:21972175, 29289479). In addition, 2 individuals were homozygous for the variant (2 x 0.5 points. PMID:36572041, Revvity Omics Clinical Laboratory data) (PM3_Strong). Two more patients have been described with the variant and another variant, either c.-32-17_-32-10delinsT CCCTGCTGAGCCTCCTACA GGCCTCCCGC (PMID:25687635) or c.569G>A (p.Arg190His) (PMID:23000108). The allelic data from these patients will be used in the classification the second variant and is not included here to avoid circular logic. At least 4 individuals have GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts / or were reported to be on enzyme replacement therapy for Pompe disease (PMIDs: 23000108, 36572041, 33073009) (PP4_Moderate). This variant has a minor allele frequency of 0.00010(1/10306) in the African population in gnomAD v2.1.1, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Expression of the variant in COS7 cells resulted in 0% GAA activity in cells and 0% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID:18425781)(PS3_Moderate). The computational predictor REVEL gives a score of 0.822 which is above the thresholds predicting a damaging (>0.7) impact on GAA function and therefore meets this criterion (PS3). There is a ClinVar entry for this variant (Variation ID: 285157). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specification of the ClinGen Lysosomal Diseases VCEP: PS3_moderate, PM2_supporting, PM3_strong, PP3, PP4_moderate.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815349/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8 U:1
• Conservation: PhyloP100: 9.40

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.1447G>A	p.Gly483Arg	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.1447G>A	p.Gly483Arg	missense_variant	10/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250890 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135766

Gnomad AFR exome AF: 0.0000617

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461644 Hom.: 0 Cov.: 37 AF XY: 0.0000124 AC XY: 9 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The heterozygous p.Gly483Arg variant in GAA has been reported in 5 individuals with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 19588081, 24383498, 23000108), and has been identified in 0.006% (1/16208) of African chromosomes and 0.001% (1/113308) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770590394). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported as a VUS by EGL Genetic Diagnostics, likely pathogenic variant by Counsyl, and pathogenic by Invitae in ClinVar (Variation ID: 285157). In vitro functional studies provide some evidence that the p.Gly483Arg variant may impact protein function (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. A rare, likely pathogenic variant at the the same position, p.Gly483Val, has been reported in association with disease, slightly supporting that a change at this position may not be tolerated (PMID: 22644586, 31193175). This variant has been reported in combination with other variants associated with disease and in individuals with Glycogen Storage Disease II (PMID: 19588081, 24383498, 23000108; Variation ID: 371622, 4027, 188809). The phenotype of the 2 compound heterozygous siblings is highly specific for Glycogen Storage Disease II based on GAA activity assays with muscle and fibroblast cells as well as a Western Blot with fibroblast cells (PMID: 23000108). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3, PP4, PM5_Supporting (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 10, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2020	Variant summary: GAA c.1447G>A (p.Gly483Arg) 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 8e-06 in 250890 control chromosomes (gnomAD). c.1447G>A has been reported in the literature in the compound heterozygous and homozygous state, in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Kroos_2008, Ebrahim_2012, Wens_2012, Verma_2017, Kishnani_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant causes a considerable reduction in GAA enzyme activity (e.g. Kroos_2008, Wens_2012). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 483 of the GAA protein (p.Gly483Arg). This variant is present in population databases (rs770590394, gnomAD 0.007%). This missense change has been observed in individual(s) with Pompe disease (PMID: 18425781, 19588081, 21972175, 23000108, 29122469). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 285157). 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, 23000108). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 07, 2024	The NM_000152.5:c.1447G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 483 (p.Gly483Arg). At least 7 individuals with this variant have been reported to have Pompe disease. Of these individuals, 3 were compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, with unknown phase, including c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (0.5 points, PMID: 30214072, 33073009), c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (0.5 points, PMID: 33073009), and c.32-13T>G (ClinVar Variation ID: 4027) (0.5 points, PMID: 21972175, 29289479). In addition, 2 individuals were homozygous for the variant (2 x 0.5 points. PMID: 36572041, Revvity Omics Clinical Laboratory data) (PM3_Strong). Two more patients have been described with the variant and another variant, either c.-32-17_-32-10delinsT CCCTGCTGAGCCTCCTACA GGCCTCCCGC (PMID: 25687635) or c.569G>A (p.Arg190His) (PMID: 23000108). The allelic data from these patients will be used in the classification the second variant and is not included here to avoid circular logic. At least 4 individuals have GAA activity <10% normal in lymphocytes/leukocytes/muscle samples/<30% normal in cultured fibroblasts / or were reported to be on enzyme replacement therapy for Pompe disease (PMIDs: 23000108, 36572041, 33073009) (PP4_Moderate). This variant has a minor allele frequency of 0.00010(1/10306) in the African population in gnomAD v2.1.1, which is lower than the ClinGen Lysosomal Diseases VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Expression of the variant in COS7 cells resulted in 0% GAA activity in cells and 0% in medium, and evidence of abnormal synthesis and processing on Western blot, indicating that this variant may impact protein function (PMID: 18425781)(PS3_Moderate). The computational predictor REVEL gives a score of 0.822 which is above the thresholds predicting a damaging (>0.7) impact on GAA function and therefore meets this criterion (PS3). There is a ClinVar entry for this variant (Variation ID: 285157). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specification of the ClinGen Lysosomal Diseases VCEP: PS3_moderate, PM2_supporting, PM3_strong, PP3, PP4_moderate. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 2024) -

not provided Uncertain:1

Uncertain significance, flagged submission

clinical testing

Eurofins Ntd Llc (ga)

Dec 08, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.82
Sift	Benign	0.030	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.98		Loss of ubiquitination at K479 (P = 0.0797);Loss of ubiquitination at K479 (P = 0.0797);
MVP		1.0
MPC		0.59
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs770590394; hg19: chr17-78084535;