chr17-80112666-G-A

Position:

chr17-80112666-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PM2_SupportingPM3_StrongPS3_SupportingPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.1843G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 615 (p.Gly615Arg). At least 7 patients with a diagnosis of Pompe disease have been reported with this variant. Five of these patients are reported to have infantile onset Pompe disease (IOPD) and meet the criteria for PP4_Moderate with <10% GAA activity in cultured fibroblasts and/or GAA activity in the affected range in leukocytes (PMIDs: 15366815, 16860134, 18458862, 25037089), documented symptoms consistent with IOPD, and on enzyme replacement therapy (PMIDs: 16860134, 25037089) (PP4_Moderate). Of the reported patients, three are compound heterozygous, phase unknown, for another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, either c.2238G>A (p.Trp746Ter) (PMID:16860134) or c.1935C>A (p.Asp645Glu) (PMID:18458862) (2 patients). Two patients are homozygous for the variant (PMID:15366815, 25037089) (PM3_Strong). A further two patients are compound heterozygous for the variant and either c.1832G>A (p.Gly611Asp) (PMID:24269976) or c.1933G>C (p.Asp645His (clinical laboratory data) . The allelic data from these patients will be used in the classification of the other variant and is not included here to avoid circular. Finally, An 4 patients have been reported in the literature but the data was not included because the cDNA change for the variant was not provided, or does not match amino acid change (PMIDs: 10338092, 18607768, 21757382). The highest population minor allele frequency in gnomAD is 0.00022 in the East Asian 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, the variant resulted in <2% GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.989 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: 188746, 2 star review status), with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Verions 2.0): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA273955/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 9.80

Variant links:

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]

GAA links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS3

PM2

PM3

PP3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.1843G>A	p.Gly615Arg	missense_variant	13/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.1843G>A	p.Gly615Arg	missense_variant	13/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

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:

0.0000164

AC:

AN:

243962

Hom.:

AF XY:

0.00000751

AC XY:

AN XY:

133124

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000222

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459872

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2018	Variant summary: GAA c.1843G>A (p.Gly615Arg) 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 2.1e-05 in 97298 control chromosomes (gnomAD and publication). The variant, c.1843G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), whom presented with significantly decreased enzyme activity (<10%). 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843). 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. ClinVar contains an entry for this variant (Variation ID: 188786). This missense change has been observed in individual(s) with Pompe disease (PMID: 10338092, 15366815, 16860134, 18458862, 18607768, 21757382, 24269976, 25037089). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs549029029, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 615 of the GAA protein (p.Gly615Arg). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 14, 2021	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 06, 2022	The NM_000152.5: c.1843G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 615 (p.Gly615Arg). At least 7 patients with a diagnosis of Pompe disease have been reported with this variant. Five of these patients are reported to have infantile onset Pompe disease (IOPD) and meet the criteria for PP4_Moderate with <10% GAA activity in cultured fibroblasts and/or GAA activity in the affected range in leukocytes (PMIDs: 15366815, 16860134, 18458862, 25037089), documented symptoms consistent with IOPD, and on enzyme replacement therapy (PMIDs: 16860134, 25037089) (PP4_Moderate). Of the reported patients, three are compound heterozygous, phase unknown, for another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, either c.2238G>A (p.Trp746Ter) (PMID: 16860134) or c.1935C>A (p.Asp645Glu) (PMID: 18458862) (2 patients). Two patients are homozygous for the variant (PMID: 15366815, 25037089) (PM3_Strong). A further two patients are compound heterozygous for the variant and either c.1832G>A (p.Gly611Asp) (PMID: 24269976) or c.1933G>C (p.Asp645His (clinical laboratory data) . The allelic data from these patients will be used in the classification of the other variant and is not included here to avoid circular. Finally, An 4 patients have been reported in the literature but the data was not included because the cDNA change for the variant was not provided, or does not match amino acid change (PMIDs: 10338092, 18607768, 21757382). The highest population minor allele frequency in gnomAD is 0.00022 in the East Asian 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, the variant resulted in <2% GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.989 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: 188746, 2 star review status), with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Verions 2.0): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	May 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 24, 2024	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gly615Arg variant in GAA has been reported in 13 individuals (including 4 Taiwanese, 1 Chinese, and 1 German individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 16860134, 18458862, 10338092, 24269976, 21232767, 20080426, 15366815, 18607768, 21757382, 25037089), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae and Integrated Genetics in ClinVar (Variation ID: 188786). This variant has been identified in 0.022% (4/17994) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs549029029). 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.Gly615Arg variant may impact protein function (PMID: 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 in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly615Arg variant is pathogenic (PMID: 16860134, 18458862). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 21757382, 16860134, 18458862). 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, low frequency in the general population, and multiple occurrences in combination with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2022	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: 18458862, 21757382, 24269976, 11738358, 31254424, 15366815, 18301443, 20080426, 12394636, 16860134, 19862843, 11949932, 29046207, 31953985, 30275481, 32711049, 32014045, 31086307, 21232767, 10338092, 18607768) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

.;D

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

5.2

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.6

D;D

REVEL

Pathogenic

0.99

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

1.0

MutPred

0.97

Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);

MVP

1.0

MPC

0.59

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over