17-80112625-C-T

Variant names:

• chr17-80112625-C-T
• rs374470794
• NM_000152.5:c.1802C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3 PM2_Supporting PS3_Moderate PM3_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c. c.1802C>T variant in GAA is a missense variant predicted to cause substitution of serine by leucine at amino acid 601 (p.Ser601Leu). At least eight patients with this variant have been reported to have Pompe disease including three with clinical features consistent with infantile onset Pompe disease and on enzyme replacement therapy (PMID 22538254, 30023291), and one with GAA deficiency reported in the affected range in lymphocytes (PMID 22676651), as well as four patients reported to be diagnosed with the condition (PMID 28394184) (PP4_Moderate). Of note, in one patient, with features of infantile onset Pompe disease and on ERT, the variant was reported to be in cis with pseudodeficiency variants c.1726G>A and c.2065G>A (PMID 22538254). Of these patients, four were compound heterozygous for the variant and a variant that has been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PMID 22676651, 28394184, 30023291) One patient was homozygous for the variant (PMID 30023291) (PM3_Strong). In addition, three patients were compound heterozygous for the variant and a missense variant (PMID 22538254, 28394184). The in trans data from these patients will be used in the assessment of the second variant and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD is 0.00064 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 0.5% wild type GAA activity in cells and medium, and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe"). This indicates that the variant may impact protein function (PMID:22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1802C>G (p.Ser601Trp), in the same codon has been reported in patients with Pompe disease (PMID 17056254, 29422078). However, the data for p.Ser601Leu will be used in the assessment of p.Ser601Trp and therefore PM5 is not met here in order to avoid circular logic (PM5 not met). The is a ClinVar entry for this variant (Variation ID: 194154). In summary, this variant meets the criteria to be classified at pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (Specification version 2.0): PM3_Strong; PS3_Moderate, PP4_Moderate, PM2_Supporting, PP3.(Classification approved on August 17, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA274982/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 7.75
• Publications: 29 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 10 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.1802C>T	p.Ser601Leu	missense_variant	Exon 13 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1802C>T	p.Ser601Leu	missense_variant	Exon 13 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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: 0.00000274 AC: 4 AN: 1460668 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726684

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111938

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:8

Apr 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 601 of the GAA protein (p.Ser601Leu). This variant is present in population databases (no rsID available, gnomAD 0.06%). This missense change has been observed in individuals with Pompe disease (PMID: 22252923, 28394184). ClinVar contains an entry for this variant (Variation ID: 194154). 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: 22644586). For these reasons, this variant has been classified as Pathogenic. -

Sep 07, 2021

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c. c.1802C>T variant in GAA is a missense variant predicted to cause substitution of serine by leucine at amino acid 601 (p.Ser601Leu). At least eight patients with this variant have been reported to have Pompe disease including three with clinical features consistent with infantile onset Pompe disease and on enzyme replacement therapy (PMID 22538254, 30023291), and one with GAA deficiency reported in the affected range in lymphocytes (PMID 22676651), as well as four patients reported to be diagnosed with the condition (PMID 28394184) (PP4_Moderate). Of note, in one patient, with features of infantile onset Pompe disease and on ERT, the variant was reported to be in cis with pseudodeficiency variants c.1726G>A and c.2065G>A (PMID 22538254). Of these patients, four were compound heterozygous for the variant and a variant that has been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PMID 22676651, 28394184, 30023291) One patient was homozygous for the variant (PMID 30023291) (PM3_Strong). In addition, three patients were compound heterozygous for the variant and a missense variant (PMID 22538254, 28394184). The in trans data from these patients will be used in the assessment of the second variant and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD is 0.00064 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). Expression of the variant in COS cells resulted in 0.5% wild type GAA activity in cells and medium, and evidence of abnormal GAA synthesis and processing, leading the variant to be described as Class B (“potentially less severe"). This indicates that the variant may impact protein function (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant, c.1802C>G (p.Ser601Trp), in the same codon has been reported in patients with Pompe disease (PMID 17056254, 29422078). However, the data for p.Ser601Leu will be used in the assessment of p.Ser601Trp and therefore PM5 is not met here in order to avoid circular logic (PM5 not met). The is a ClinVar entry for this variant (Variation ID: 194154). In summary, this variant meets the criteria to be classified at pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (Specification version 2.0): PM3_Strong; PS3_Moderate, PP4_Moderate, PM2_Supporting, PP3. (Classification approved on August 17, 2021) -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM3_VeryStrong+PP4_Moderate+PS3_Moderate -

Jul 27, 2021

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.1802C>T (p.Ser601Leu) 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 1.3e-05 in 150998 control chromosomes (gnomAD). c.1802C>T has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) from different ethnicities (e.g. Chen_2017, Bali_2012, Herzog_2012, Monies_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant caused a significant decrease in protein levels and in enzymatic activity (Kroos_2012). Two 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 (n=1) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

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.Ser601Leu variant in GAA has been reported in 2 Saudi Arabian and 1 German individuals with Glycogen Storage Disease II (PMID: 30023291, 22676651) and has also been reported pathogenic by EGL in ClinVar (Variation ID: 194154). This variant has been identified in 0.062% (1/1620) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs374470794). 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.Ser601Leu variant may impact GAA activity and protein levels (PMID: 22644586). 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 additional variant at the the same position, p.Ser601Trp, has been curated likely pathogenic by our study, slightly supporting that a change at this position may not be tolerated (Variation ID: 501793; PMID: 17056254). The presence of this variant in combination with a reported pathogenic variant in an individual with Glycogen Storage Disease II slightly increases the likelihood that the p.Ser601Leu variant is pathogenic (PMID: 22676651). The phenotype of a compound heterozygous variant is highly specific for Glycogen Storage Disease II based on GAA activity assays with lymphocytes (PMID: 22676651). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3_Supporting, PM2, PM5_Supporting, PP3, PP4 (Richards 2015). -

Feb 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser601Leu has been reported in at least 8 individuals with Pompe disease, several of whom were either compound heterozygous with a pathogenic/likely pathogenic variant or homozygous (Herzog 2012 PMID: 22676651, Chen 2017 PMID: 28394184, Al-Hassnan 2018 PMID: 30023291). It has also been identified in 0.02% (1/5194)) of East Asian chromosomes by gnomAD, v. 3 (http://gnomad.broadinstitute.org). The variant has been reported in clinvar (Variation ID 194154), and is classified as pathogenic by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel. In vitro studies provide evidence that the variant may impact normal protein activity (Kroos 2012 PMID: 22644586), and computation tools also predict an impact to the protein. In addition, a second variant at the same amino acid position (Ser601Trp) has also been reported in patients with Pompe disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pompe disease. ACMG/AMP criteria applied: PM3_Strong, PM5, PS3_Moderate, PM2_Supporting, PP3, PP4. -

Dec 25, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:2

Nov 19, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	H;H
PhyloP100		7.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.87		Loss of glycosylation at S601 (P = 0.0225);Loss of glycosylation at S601 (P = 0.0225);
MVP		1.0
MPC		0.51
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.95
Mutation Taster		=2/98	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: rs374470794; hg19: chr17-78086424;