rs765362308

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4_ModeratePM3PM2_SupportingPS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1710C>G (p.Asn570Lys) variant in GAA has a minor allele frequency in gnomAD of 0.0001149 in the African population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. At least three individuals have been reported with this variant and documented GAA activity in the affected range and/or were reported to be on enzyme replacement therapy for Pompe disease (PMID:17151339, 22538254, 29122469, 32248831) (PP4_Moderate). This variant was found in compound heterozygosity with another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP including c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1), phase unconfirmed, in at least one patient with Pompe disease (PMID:22538254, 22658377, 29122469, 31193175)(0.5 points), and confirmed in trans in a patient with c.953T>C (p.Met318Thr) (ClinVar Variation ID: 4021; SCV002583364.1) (PMID:36636589) (1 point). Another patient with the variant, along with with c.-32-13T>G and a rare synonymous variant c.1923G>A (p.Leu641=) has been reported (PMID:32248831). While the allelic data from the latter patient is likely supportive of pathogenicity for c.1710C>G (p.Asn570Lys), it is not included here because the impact of p.Leu641= is unknown (Total 1.5 points) (PM3). Functional assays support a deleterious effect of this variant. When expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.9% GAA activity in cells and 0.5% in medium, and evidence of abnormal synthesis and processing on Western blot (PS3_Moderate). Computational evidence is inconclusive, REVEL score = 0.662 which is lower than the LD VCEP threshold for PP3 (>0.7) but higher than the LD VCEP threshold for BP4 (<0.5), and therefore does not meet either criterion. There is a ClinVar entry for this variant (Variation ID: 555153). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel. GAA-specific GAA-specific ACMG/AMP criteria met (Specifications Version 2.0): PS3_Moderate, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 22, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA401369044/MONDO:0009290/010

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:6U:1

Conservation

PhyloP100: 4.49

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 7 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.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.1710C>G	p.Asn570Lys	missense_variant	Exon 12 of 20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.1710C>G	p.Asn570Lys	missense_variant	Exon 12 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727206

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.0000113

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:5Uncertain:1

Nov 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.1710C>G (p.Asn570Lys) 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 was absent in 251344 control chromosomes (gnomAD). c.1710C>G has been reported in combination with another GAA variant in the literature in individuals affected with infantile-onset Pompe disease or late-onset Pompe disease (Banugaria_2011, Kishnani_2019, Vanherpe_2020, De Groot_2021). These data indicate that the variant is likely to be associated with disease. At least one functional paper reports experimental evidence evaluating an impact on protein function and this variant results in reducing alpha-glucosidase activity in transfected cells compared to WT activity (Kroos_2012). The following publications have been ascertained in the context of this evaluation (PMID: 21637107, 30711607, 34220802, 31193175, 31086307, 18425781, 22644586, 29122469, 31254424, 22658377, 33717985, 22538254, 36636589, 29061980, 30281819, 32248831). ClinVar contains an entry for this variant (Variation ID: 555153). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Oct 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 570 of the GAA protein (p.Asn570Lys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with Pompe disease (PMID: 18425781, 22658377, 29122469, 31086307). ClinVar contains an entry for this variant (Variation ID: 555153). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on GAA function (PMID: 22644586). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Nov 19, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.1710C>G (p.Asn570Lys) variant in GAA has a minor allele frequency in gnomAD of 0.0001149 in the African population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion. At least three individuals have been reported with this variant and documented GAA activity in the affected range and/or were reported to be on enzyme replacement therapy for Pompe disease (PMID: 17151339, 22538254, 29122469, 32248831) (PP4_Moderate). This variant was found in compound heterozygosity with another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP including c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1), phase unconfirmed, in at least one patient with Pompe disease (PMID: 22538254, 22658377, 29122469, 31193175)(0.5 points), and confirmed in trans in a patient with c.953T>C (p.Met318Thr) (ClinVar Variation ID: 4021; SCV002583364.1) (PMID: 36636589) (1 point). Another patient with the variant, along with with c.-32-13T>G and a rare synonymous variant c.1923G>A (p.Leu641=) has been reported (PMID: 32248831). While the allelic data from the latter patient is likely supportive of pathogenicity for c.1710C>G (p.Asn570Lys), it is not included here because the impact of p.Leu641= is unknown (Total 1.5 points) (PM3). Functional assays support a deleterious effect of this variant. When expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.9% GAA activity in cells and 0.5% in medium, and evidence of abnormal synthesis and processing on Western blot (PS3_Moderate). Computational evidence is inconclusive, REVEL score = 0.662 which is lower than the LD VCEP threshold for PP3 (>0.7) but higher than the LD VCEP threshold for BP4 (<0.5), and therefore does not meet either criterion. There is a ClinVar entry for this variant (Variation ID: 555153). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel. GAA-specific GAA-specific ACMG/AMP criteria met (Specifications Version 2.0): PS3_Moderate, PM3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 22, 2024). -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Asn570Lys variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 29122469, 22658377, 18425781, 22538254) and has been identified in 0.011% (1/8702) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765362308). 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 also been reported in ClinVar as a VUS by Counsyl (VariationID: 555153). In vitro functional studies using COS-7 cells transfected with the variant provide some evidence that the p.Asn570Lys variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <1% of wild type, consistent with disease (PMID: 17151339). Computational prediction tools do not provide strong support for or against an impact to the protein, but the Asn at position 570 is not conserved in mammals or evolutionary distant species, raising the possibility that a change at this position may be tolerated. However, the presence of this variant in combination with reported pathogenic variant p.Arg584Ter (VariationID: 4034, PMID: 29122469, 22658377, 22538254) and in an individual with glycogen storage disease II increases the likelihood that the p.Asn570Lys variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PM3_Supporting PP4 (Richards 2015). -

not provided

Pathogenic:1

Dec 25, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

.;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.9

L;L

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.95

P;P

Vest4

0.87

MutPred

0.89

Gain of ubiquitination at N570 (P = 0.0351);Gain of ubiquitination at N570 (P = 0.0351);

MVP

0.97

MPC

0.54

ClinPred

0.99

GERP RS

3.4

Varity_R

0.94

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: 1

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