17-80117015-G-C

Variant names:

• chr17-80117015-G-C
• rs752921215
• NM_000152.5:c.2237G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PM2_Supporting PM5 PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2237G>C variant in GAA is a missense variant predicted to result in the substitution of tryptophan by serine at amino acid 746 (p.Trp746Ser). This variant has been reported in at least 11 patients with late onset Pompe disease (LOPD) (PMID:18425781, 22081099, 24169249, 28490439, 33344388, 34020684), with two having GAA enzyme activity <10% in muscle (PMID:22081099) (PP4_Moderate). One Chinese patient with LOPD was compound heterozygous for the variant and a nonsense pathogenic variant c.2237G>A (p.Trp746*) at the same nucleotide; however, this patient has a third variant c.503G>A (p.Arg168Gln) with no phase information (PMID:24169249), so it's not used for PM3 point counting. Another Chinese patient was compound heterozygous for the variant (maternally inherited) and a pathogenic variant c.1935C>A (p.Asp645Glu) (paternally inherited) (PMID:33344388); and it's not used for PM3 point counting due to the complex phenotype and the lack other evidence supporting the diagnosis of LOPD. A third Chinese individual heterozygous for the variant, a pathogenic variant c.2662G>T (p.Glu888*), and a third variant c.2647-7G>A was detected by genome sequencing as newborn screening; and it's not used for PM3 point counting due to the lack of phenotype information. Six Italian patients (PMID:22081099) and one Spanish patient (PMID:34020684) with LOPD were heterozygous for the variant and c.-32-13T>G pathogenic variant with no phase information (1 point, max for homozygous patients) (PM3). Expression of the variant in COS or HEK293 cells resulted in 2% residual GAA activity in medium and 0.1% normal activity in cells and evidence of abnormal GAA synthesis and processing, leading to a Class B ("potentially less severe") classification (PMID:22644586). However, another in vitro study reported the variant as a "relatively mild mutation" but also class E "probably non-pathogenic" (PMID:23430493). Functional criteria is not applied due to inconsistent functional classification. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001733 (13/75034) in the African/African American population which is lower than the ClinGen Lysosomal Diseases Variant Curation Expert Panel (LD VCEP) threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.919 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). A different missense variant c.2238G>C (p.Trp746Cys) on the same amino acid has been classified as pathogenic by the LD VCEP (PM5). There is a ClinVar entry for this variant (Variation ID: 188484; 2 star review status) with 7 submitters classifying the variant as pathogenic and 5 as likely pathogenic. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PM3, PM5, PP4_Moderate, PP3, PM2_Supporting. (Classification approved by the ClinGen LD VCEP - Dec. 17, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA198797/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 9.45
• Publications: 56 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.2237G>C	p.Trp746Ser	missense	Exon 16 of 20	NP_000143.2
	GAA	NM_001079803.3		c.2237G>C	p.Trp746Ser	missense	Exon 17 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.2237G>C	p.Trp746Ser	missense	Exon 16 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.2237G>C	p.Trp746Ser	missense	Exon 16 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.2237G>C	p.Trp746Ser	missense	Exon 17 of 21	ENSP00000374665.3
	GAA	ENST00000933406.1		c.2252G>C	p.Trp751Ser	missense	Exon 16 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000678 AC: 17 AN: 250744 AF XY: 0.0000516

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461216 Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 726926

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52886

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

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111890

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74466

African (AFR) AF: 0.000168 AC: 7 AN: 41556

American (AMR) AF: 0.000327 AC: 5 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000160 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	-	-	Glycogen storage disease, type II (10)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-14	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Gain of glycosylation at W746 (P = 0.0151)
MVP		0.97
MPC		0.69
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.93
Mutation Taster		=3/97	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: rs752921215; hg19: chr17-78090814;