rs753269119

Positions:

chr17-80112679-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000152.5(GAA):c.1856G>A(p.Ser619Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,154 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S619R) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.79

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:

GAA (HGNC:):

GAA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a strand (size 2) in uniprot entity LYAG_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000152.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-80112680-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 17-80112679-G-A is Pathogenic according to our data. Variant chr17-80112679-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80112679-G-A is described in Lovd as [Pathogenic]. Variant chr17-80112679-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.1856G>A	p.Ser619Asn	missense_variant	13/20	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.1856G>A	p.Ser619Asn	missense_variant	13/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152036

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:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

241268

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1458998

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725696

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000175

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

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	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ser619Asn variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22194990, 26946079, 22980766, 16838077, 24158270, 25052852, 23668440, 25998610). This variant has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370146) and has been identified in 0.013% (4/29974) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753269119). 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.Ser619Asn variant may impact proteolytic activation of GAA and GAA activity (PMID: 16838077, 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. One pathogenic additional variant at the the same position, p.Ser619Arg, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 550825). The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Ser619Asn variant is pathogenic (PMID: 16838077). Of note, this variant has also been observed in cis with the known pathogenic variant c.-32-13T>G with both variants in the homozygous state in an individual with Glycogen Storage Disorder II (PMID: 26946079). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissue, consistent with disease (PMID: 24158270, 26946079, 16838077). 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, another pathogenic variant at the same position, and low frequency in the general population. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3, PM3_Supporting, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 10, 2019	Variant summary: GAA c.1856G>A (p.Ser619Asn) results in a conservative amino acid change in 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 1.7e-05 in 237486 control chromosomes (gnomAD). The variant, c.1856G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Kroos_2006, Remiche_2014, Gallardo_2011, Parenti_2014, Arslan_2016). One patient, Arslan_2016, was found to be homozygous for two deleterious variants, the variant of interest and c.32-13T>G, to which the authors indicate the phenotype was more progressive. The patient was born to consanguineous Turkish parents. These data indicate that the variant may 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% of residual acid -glucosidase activity (Kroos_2006). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 30, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 619 of the GAA protein (p.Ser619Asn). This variant is present in population databases (rs753269119, gnomAD 0.01%). This missense change has been observed in individual(s) with Pompe disease (PMID: 16838077, 22990675, 24158270, 25998610, 26946079). ClinVar contains an entry for this variant (Variation ID: 370146). 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: 19862843). This variant disrupts the p.Ser619 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14643388, 21471980, 25213570, 27363342, 29124014). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Ser619Asn variant in GAA has been reported in at least 8 individuals (6 in the compound heterozygous state) with Glycogen Storage Disease II. Of note, in 2 of these individuals (one homozygote and one compound heterozygote), this variant was in cis with the known pathogenic variant c.-32-13T>G (Gallardo 2011 PMID: 22194990, Arslan 2016 PMID: 26946079, Alejaldre 2012 PMID: 22980766, Kroos 2006 PMID: 16838077, Remiche 2014 PMID: 24158270, Parenti 2014 PMID: 25052852, Fecarotta 2013 PMID: 23668440, Gutiérrez-Rivas 2015 PMID: 25998610). This variant has also been reported in ClinVar (Variation ID: 370146) and has been identified in 2/4830 of South Asian and 1/67968 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies using patient tissues provide some evidence that this variant may impact proteolytic activation of GAA and GAA activity (Kroos 2006 PMID: 16838077). 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. Another variant involving this codon (p.Ser619Arg) has been identified in individuals with autosomal recessive Glycogen Storage Disease II and is classified as likely pathogenic/pathogenic in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PM5, PP3, PM3_Very strong. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2023	Published functional studies demonstrate reduced total enzyme amount and in vitro enzyme activity (PMID: 16838077); 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: 34530085, 31589614, 33202836, 23668440, 16838077, 26946079, 31086307, 21471980, 25052852, 14643388, 19862843, 22194990, 22980766, 22990675, 27363342, 25213570, 25998610, 33073007, 29124014, 24158270) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -

Abnormality of metabolism/homeostasis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

.;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;H

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.95

MutPred

0.98

Loss of disorder (P = 0.1076);Loss of disorder (P = 0.1076);

MVP

1.0

MPC

0.52

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.94

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