rs201896815

Positions:

• chr17-80107648-G-A

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PM2_Supporting PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: This variant, NM_000152.5(GAA):c.784G>A, is predicted to result in the substitution of glutamate to lysine at amino acid 262 (p.Glu262Lys). This variant represented 6.8% of alleles in an Italian case series of 29 infants with Pompe disease (PMID:18429042). This variant has been reported in at least 20 individuals with Pompe disease, including at least 12 individuals with documented laboratory data showing deficiency of GAA activity and/or clinical symptoms consistent with infantile onset Pompe disease (cardiomegaly and muscle weakness), and/or on treated with enzyme replacement therapy (ERT) meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate (PMID 11738358, 18285536, 19588081, 19948615, 25455803, 26497565, 27344650, 29181627, 29422078, 30023291, 31193175 31915562, 33228748)(PP4_Moderate). The variant has been reported in compound heterozygosity with a pathogenic variant in at least 8 patients, phase unconfirmed (PMID:11738358, 18285536, 19948615, 24269976, 25455803, 29181627, 29422078, 29880332), and in at least 5 homozygous patients diagnosed with Pompe disease (PMIDs: 18429042, 26497565, 29422078, 33228748, 33325062) (PM3_Very Strong). More data is available in the literature but the maximum evidence for PM3_Very Strong has been reached. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, allowing this criterion to be applied (PM2_Supporting). The computational predictor REVEL gives a score of 0.888 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional studies have not been reported for this variant. There is a ClinVar entry for this variant (ClinVar variation ID: 188806) with 3 submitters classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PM3_Very Strong, PP4_Moderate, PP3, PM2_Supporting. (Classification approved: August 17, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA273984/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 7.87

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 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.784G>A	p.Glu262Lys	missense_variant	4/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.784G>A	p.Glu262Lys	missense_variant	4/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152156 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251008 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1460776 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726724

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152274 Hom.: 0 Cov.: 34 AF XY: 0.0000537 AC XY: 4 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2018	Variant summary: GAA c.784G>A (p.Glu262Lys) results in a conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 276972 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (1.4e-05 vs 0.0042), allowing no conclusion about variant significance. The c.784G>A variant has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 07, 2023	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	May 30, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 06, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 262 of the GAA protein (p.Glu262Lys). This variant is present in population databases (rs201896815, gnomAD 0.005%). This missense change has been observed in individual(s) with glycogen storage disease type II (Pompe disease) (PMID: 11738358, 18429042, 19588081, 21232767, 22658377, 27344650, 29422078, 31915562). 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: 188806). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Aug 25, 2021	This variant, NM_000152.5(GAA):c.784G>A, is predicted to result in the substitution of glutamate to lysine at amino acid 262 (p.Glu262Lys). This variant represented 6.8% of alleles in an Italian case series of 29 infants with Pompe disease (PMID: 18429042). This variant has been reported in at least 20 individuals with Pompe disease, including at least 12 individuals with documented laboratory data showing deficiency of GAA activity and/or clinical symptoms consistent with infantile onset Pompe disease (cardiomegaly and muscle weakness), and/or on treated with enzyme replacement therapy (ERT) meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate (PMID 11738358, 18285536, 19588081, 19948615, 25455803, 26497565, 27344650, 29181627, 29422078, 30023291, 31193175 31915562, 33228748)(PP4_Moderate). The variant has been reported in compound heterozygosity with a pathogenic variant in at least 8 patients, phase unconfirmed (PMID: 11738358, 18285536, 19948615, 24269976, 25455803, 29181627, 29422078, 29880332), and in at least 5 homozygous patients diagnosed with Pompe disease (PMIDs: 18429042, 26497565, 29422078, 33228748, 33325062) (PM3_Very Strong). More data is available in the literature but the maximum evidence for PM3_Very Strong has been reached. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, allowing this criterion to be applied (PM2_Supporting). The computational predictor REVEL gives a score of 0.888 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional studies have not been reported for this variant. There is a ClinVar entry for this variant (ClinVar variation ID: 188806) with 3 submitters classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PM3_Very Strong, PP4_Moderate, PP3, PM2_Supporting. (Classification approved: August 17, 2021) -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Glu262Lys variant in GAA has been reported in 14 individuals (including 6 Italian, 1 Brazilian, and 1 Chinese individuals) with Glycogen Storage Disease II (PMID: 22658377, 22980766, 26497565, 24269976, 24158270, 22958975, 22704482, 21232767, 19588081, 18429042), and has also been reported likely pathogenic by Counsyl and Invitae and pathogenic by EGL Genetic Diagnostics and Integrated Genetics in ClinVar (Variation ID: 188806). This variant has been identified in 0.005% (1/19938) of East Asian chromosomes and 0.002% (3/128794) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201896815). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. 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 the homozygous state and in combination with 1 reported pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu262Lys variant is pathogenic (PMID: 26497565, 24158270). Individuals with this variant in the heterozygous and homozygous state have a highly specific phenotype for disease based on GAA enzyme activity assays (PMID: 26497565, 24158270). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PM2, PP3, PP4 (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 10, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 31915562, 26497565, 27344650, 29422078, 29181627, 25455803, 20080426, 24269976, 22980766, 27183828, 25466677, 19588081, 18429042, 22704482, 22958975, 26830551, 22658377, 21232767, 24158270, 11738358) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
Sift4G	Uncertain	0.011	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.91, 0.91
MVP		1.0
MPC		0.57
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.99

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: rs201896815; hg19: chr17-78081447;