rs370950728

Variant names:

• chr17-80105857-G-A
• rs370950728
• NM_000152.5:c.655G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80105857-G-A
• chr17-80105857-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3 PP4 PM3_Strong PS3 PM2

This summary comes from the ClinGen Evidence Repository: This variant, c.655G>A (p.Gly219Arg), has been reported in at least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, including c.-32-13T>G (PMID 21550241, 24844452), c.169C>T (p.Gln57Ter) (PMID 29124014), or c.2560C>T (p.Arg854Ter)(PMID 23266370), and one is homozygous for the variant (PMID 25139343). This in trans data meets PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004024 in the African population, meeting PM2. When it was expressed in COS cells, this variant results in <2% wild type GAA activity and it is abnormally processed (PMIDs 14695532; 19862843), meeting PS3. The score for the REVEL in silico meta-predictor, 0.872, also supports that the variant has a deleterious impact on GAA function, meeting PP3. There is a ClinVar entry for this variant (Variation ID 189065; 2 star review status) with four submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274334/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12 U:1
• Conservation: PhyloP100: 9.71
• Publications: 40 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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	c.655G>A	p.Gly219Arg	missense_variant	Exon 3 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.655G>A	p.Gly219Arg	missense_variant	Exon 3 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 244972 AF XY: 0.00000750

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1453526 Hom.: 0 Cov.: 57 AF XY: 0.00000830 AC XY: 6 AN XY: 723044

African (AFR) AF: 0.0000299 AC: 1 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.0000213 AC: 1 AN: 47046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5444

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110638

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152200 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

African (AFR) AF: 0.0000483 AC: 2 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000601 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8 Uncertain:1

Jan 22, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Gly219Arg variant in GAA has been reported in 22 individuals (including 10 French, 3 Saudi, 1 Italian, 1 Spanish, 1 Japanese, and 3 other Caucasian individuals) with Glycogen Storage Disease II (PMID: 23787031, 30023291, 18995995, 23266370, 11738358, 21550241, 25037089, 23601496, 21637107, 29124014, 30155607, 18429042, 24844452, 14695532), and has also been reported pathogenic (by EGL, GeneDx, Invitae, and Integrated Genetics) and likely pathogenic (by Counsyl) in ClinVar (Variation ID: 189065). This variant has been identified in 0.004% (1/24848) of African chromosomes and 0.003% (1/35388) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs370950728). 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.Gly219Arg variant may reduce GAA activity by more than 98% (PMID: 14695532, 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. The presence of this variant in combination with pathogenic and likely pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly219Arg variant is pathogenic (PMID: 21637107, 21550241, 11738358). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with very low GAA activity detected in relevant tissues (PMID: 23601496, 24844452, 21550241, 29124014, 11738358, 21637107). 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 with COS cells transfected with this variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015). -

Nov 19, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 07, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GAA c.655G>A (p.Gly219Arg) variant located in the Galactose mutarotase, N-terminal barrel domain (via InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120140 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). Multiple publications have cited the variant in both compound heterozygous and homozygous Pompe disease patients, which were found to have very little GAA activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as pathogenic. -

Jan 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 219 of the GAA protein (p.Gly219Arg). 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 Pompe disease, including individuals with low alpha-glucosidase enzyme activity (less than 40% of normal) (PMID: 11738358, 14695532, 18429042, 21550241, 23266370, 23601496, 23787031, 29124014). ClinVar contains an entry for this variant (Variation ID: 189065). 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: 14695532). For these reasons, this variant has been classified as Pathogenic. -

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 18, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

This variant, c.655G>A (p.Gly219Arg), has been reported in at least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP's specifications for PP4. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, including c.-32-13T>G (PMID 21550241, 24844452), c.169C>T (p.Gln57Ter) (PMID 29124014), or c.2560C>T (p.Arg854Ter)(PMID 23266370), and one is homozygous for the variant (PMID 25139343). This in trans data meets PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004024 in the African population, meeting PM2. When it was expressed in COS cells, this variant results in <2% wild type GAA activity and it is abnormally processed (PMIDs 14695532; 19862843), meeting PS3. The score for the REVEL in silico meta-predictor, 0.872, also supports that the variant has a deleterious impact on GAA function, meeting PP3. There is a ClinVar entry for this variant (Variation ID 189065; 2 star review status) with four submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP3, PP4. -

not provided Pathogenic:3

Apr 13, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with significant reduction of enzyme activity (PMID: 33560568, 14695532); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 18429042, 34501319, 33301762, 30564623, 14695532, 21550241, 23601496, 21392261, 23266370, 20033296, 11738358, 24844452, 28648663, 31086307, 29122469, 32870709, 19343043, 22253258, 33560568, 23787031) -

Aug 14, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GAA-related disorder Pathogenic:1

Aug 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GAA c.655G>A variant is predicted to result in the amino acid substitution p.Gly219Arg. This variant was reported in the homozygous and compound heterozygous state in multiple patients with clinical and biochemical features consistent with Pompe disease (Sacconi et al. 2014. PubMed ID: 24844452, Fernandez-Hojas et al. 2002. PubMed ID: 11738358, Prakalapakorn et al. 2014. PubMed ID: 25139343, Hermans et al. 2004. PubMed ID: 14695532). Functional characterization of the variant suggests it is deleterious (Hermans et al. 2004. PubMed ID: 14695532). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. This variant is classified as pathogenic in clinvar by the majority of submitters including the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.2	.;M;M
PhyloP100		9.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.1	.;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.026	.;D;D
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		1.0	.;D;D
Vest4		0.96, 0.95
MutPred		0.78		Gain of MoRF binding (P = 0.068);Gain of MoRF binding (P = 0.068);Gain of MoRF binding (P = 0.068);
MVP		0.99
MPC		0.39
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.94
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs370950728; hg19: chr17-78079656;