rs1057516600

Positions:

chr17-80107816-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000152.5(GAA):c.875A>G(p.Tyr292Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,611,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.05

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 17-80107816-A-G is Pathogenic according to our data. Variant chr17-80107816-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80107816-A-G is described in Lovd as [Pathogenic]. Variant chr17-80107816-A-G is described in Lovd as [Likely_pathogenic]. Variant chr17-80107816-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.875A>G	p.Tyr292Cys	missense_variant	5/20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.875A>G	p.Tyr292Cys	missense_variant	5/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000815

AC:

AN:

245506

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133638

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000584

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459652

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726160

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Oct 15, 2020	The variant c.875A >G in exon 5 has been reported by Castro- Gago et. al . 1999 PMID:10528311 -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 26, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2018	Variant summary: GAA c.875A>G (p.Tyr292Cys) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 8.3e-06 in 241494 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (8.3e-06 vs 0.0042), allowing no conclusion about variant significance. The variant, c.875A>G, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Gort_2007, Gutierrez-Rivas_2015, Hermans_2004, Park_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 03, 2023	ClinVar contains an entry for this variant (Variation ID: 370577). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 292 of the GAA protein (p.Tyr292Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with glycogen storage disease type II (PMID: 10528311, 21940687, 23884227, 25213570). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 22, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Tyr292Cys variant in GAA has been reported in 8 individuals (including 3 Spanish, 2 Dutch, 2 Korean, and 1 Dominican/Caucasian individuals) with Glycogen Storage Disease II (PMID: 10528311, 25998610, 17616415, 14695532, 23884227, 11927738), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL Genetic Diagnostics and Integrated Genetics in ClinVar (Variation ID: 370577). This variant has been identified in 0.006% (2/34222) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516600). 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 with COS cells transfected with this variant provide some evidence that the p.Tyr292Cys variant may impact GAA activity (PMID: 19862843, 14695532, 11927738). 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 pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Tyr292Cys variant is pathogenic (PMID: 10528311, 17616415). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity detected by assays of relevant tissues, consistent with disease (PMID: 17616415, 11927738, 10528311). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on evidence from in vitro functional studies and multiple occurrences with variants associated with disease in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3, PM2, PP3, PP4 (Richards 2015). -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 27, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;H

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-8.3

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.95

Loss of disorder (P = 0.0998);Loss of disorder (P = 0.0998);

MVP

1.0

MPC

0.61

ClinPred

1.0

GERP RS

5.3

Varity_R

0.97

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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