rs374143224

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4_ModeratePS3_SupportingPP3PM3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.1979G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 660 (p.Arg660His). More than nine individuals with features consistent with Pompe disease have been reported with this variant. Of these patients 3 probands (and two siblings) have documented laboratory values indicating GAA deficiency in the affected range in dried blood spot, or muscle, or <1% activity in cultured skin fibroblasts (PMID:21484825, 25037089, 27649523), and three probands are reported to have low GAA activity and to be on enzyme replacement therapy (PP4_Moderate). Six patients are compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP. For two patients, the second variant was confirmed in trans by parental testing - c.525delT (PMID:30559630, possibly same case in PMID:30214072), and c.670C>T (p.Arg224Trp) (PMID:14643388) – and in four patients the phase of the second variant is unconfirmed - c.655G>A (p.Gly219Arg) (PMID:29122469), c.1082C>T (p.Pro361Leu) (PMID:21484825), c.1998C>T (p.Arg600Cys) (PMID:14643388), and c.2560C>T (p.Arg854Ter) (PMID:30214072). Two homozygous siblings have also been reported (PMID:27649523) (PM3_Very Strong). Two probands have been reported who are compound heterozygous for the variant and either c.-32-17_-32-10del8ins30 (PMID:25037089; two affected siblings), or c.1114C>T (p.His372Tyr) (PMID:30214072). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00025 (6/23566) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In two independent studies, in which the variant was expressed in COS cells, the GAA activity was <2% wild type, indicating that the variant has a damaging effect on GAA function (PS3_Supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant, c.1978C>T (p.Arg660Cys), has been reported at this position. p.Arg660His will be used to support the classification of p.Arg660Cys and thus PM5 is not applied here, in order to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 189172; 2 star review status) with nine submitters classifying the variant as pathogenic, and three as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting.(Approved by LSD VCEP on Feb 15, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA274455/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:16

Conservation

PhyloP100: 9.86

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 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.

PP3

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.1979G>A	p.Arg660His	missense_variant	Exon 14 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.1979G>A	p.Arg660His	missense_variant	Exon 14 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000250

AC:

AN:

240400

Hom.:

AF XY:

0.0000229

AC XY:

AN XY:

130940

show subpopulations

Gnomad AFR exome

AF:

0.000202

Gnomad AMR exome

AF:

0.0000887

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:

0.0000220

AC:

AN:

1457548

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

724832

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000677

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:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000972

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:9

Mar 01, 2022

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5: c.1979G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 660 (p.Arg660His). More than nine individuals with features consistent with Pompe disease have been reported with this variant. Of these patients 3 probands (and two siblings) have documented laboratory values indicating GAA deficiency in the affected range in dried blood spot, or muscle, or <1% activity in cultured skin fibroblasts (PMID: 21484825, 25037089, 27649523), and three probands are reported to have low GAA activity and to be on enzyme replacement therapy (PP4_Moderate). Six patients are compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP. For two patients, the second variant was confirmed in trans by parental testing - c.525delT (PMID: 30559630, possibly same case in PMID: 30214072), and c.670C>T (p.Arg224Trp) (PMID: 14643388) – and in four patients the phase of the second variant is unconfirmed - c.655G>A (p.Gly219Arg) (PMID: 29122469), c.1082C>T (p.Pro361Leu) (PMID: 21484825), c.1998C>T (p.Arg600Cys) (PMID: 14643388), and c.2560C>T (p.Arg854Ter) (PMID: 30214072). Two homozygous siblings have also been reported (PMID: 27649523) (PM3_Very Strong). Two probands have been reported who are compound heterozygous for the variant and either c.-32-17_-32-10del8ins30 (PMID: 25037089; two affected siblings), or c.1114C>T (p.His372Tyr) (PMID: 30214072). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00025 (6/23566) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In two independent studies, in which the variant was expressed in COS cells, the GAA activity was <2% wild type, indicating that the variant has a damaging effect on GAA function (PS3_Supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant, c.1978C>T (p.Arg660Cys), has been reported at this position. p.Arg660His will be used to support the classification of p.Arg660Cys and thus PM5 is not applied here, in order to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 189172; 2 star review status) with nine submitters classifying the variant as pathogenic, and three as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Approved by LSD VCEP on Feb 15, 2022). -

Jul 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2024

Genomic Diagnostics Laboratory, National Institute of Medical Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The genetic variant c.1979G>A (p.Arg660His) has a low allele frequency from exomes and genomes of the gnomAD database, and in a heterozygous state, consistent with inheritance model. Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 14643388). This variant has been extensively published elsewhere in relation to the phenotype of Glycogen storage disease, type II or Pompe disease. -

Mar 09, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.1979G>A (p.Arg660His) 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 0.00013 in 31000 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00013 vs 0.0042), allowing no conclusion about variant significance. c.1979G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Pipo_2003, Bernstein_2010, Bali_2011). These data indicate that the variant is likely to be associated with disease. At least two publications reports experimental evidence evaluating an impact on enzyme activity (Pipo_2003, Bali_2011). The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2015

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 660 of the GAA protein (p.Arg660His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) and/or Pompe disease (PMID: 14643388, 20472203, 20638881, 21484825, 22521436, 22555271, 27649523). 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: 189172). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 14643388). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:6

Nov 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 27, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 06, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 14643388); 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: 31086307, 31127727, 30559630, 33073007, 29122469, 14643388, 22555271, 22658377, 19862843, 22521436, 21484825, 26402642, 30281819, 20472203, 20638881, 34852371, 22253258, 19343043, 27649523) -

GAA-related disorder

Pathogenic:1

Jan 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GAA c.1979G>A variant is predicted to result in the amino acid substitution p.Arg660His. This variant was reported in the homozygous and compound heterozygous states in multiple patients with Pompe disease (Nazari et al. 2017. PubMed ID: 27649523, Pipo et al. 2003. PubMed ID: 14643388, Kindel et al. 2012. PubMed ID: 22555271). In at least two patients carrying this variant, biochemical testing indicated GAA deficiency (Nazari et al. 2017. PubMed ID: 27649523). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD. This variant was classified as pathogenic by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel and most laboratories in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/189172/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

H;H

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.98

MVP

1.0

MPC

0.60

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.96

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