NM_000152.5:c.1935C>A

Variant names:

• chr17-80112922-C-A
• rs28940868
• NM_000152.5:c.1935C>A

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PS3_Moderate PM3 PM5 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1935C>A variant in GAA is a missense variant predicted to cause substitution of aspartate by glutamate at amino acid 645 (p.Asp645Glu). At least 50 individuals with this variant have been reported with GAA activity in the affected range for Pompe disease in fibroblasts, lymphocytes, or dried blood spots (PMID:8094613, 9554747, 18458862). This variant is reported to be the most common variant identified in patients with infantile onset Pompe disease from China, Taiwan, and Thailand (PMID 9554747, 18458862, 21039225, 31342611), although it has also been reported in other populations (PMID:8094613). It has been found to be associated with a specific haplotype, which includes the pseudodeficiency variant, indicating that it is a founder variant (PMID:9554747). However, other studies have not found an association with this specific haplotype (PMID:8094613, 18458862) (PP4_Moderate). This variant was found in compound heterozygosity with a pathogenic variant in 5 patients (PMID:8094613, 9554747, 18458862, 28394184), as well as over 30 homozygotes (PMID:9554747, 18458862, 28394184). More data is available in the literature but the maximum amount of evidence required for PM3_Strong has been reached. The highest population minor allele frequency in gnomAD is 0.001729 in the East Asian population. This is higher than the ClinGen LSD VCEP threshold (<0.001) for PM2, and therefore does not meet this criterion. The computational predictor REVEL gives a score of 0.8, which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Measurement of GAA activity in COS cells transfected with the variant showed <10% normal GAA activity indicating that this variant impacts protein function (PMID:8094613, 19862843). In addition, little to no mature 76 kDa protein was detected by pulse-chase analysis, suggesting abnormal synthesis and/or processing of the protein (PMID:8094613) (PS3_Moderate). Another missense variant, c.1933G>A (p.Asp645Asn) (ClinVar Variation ID: 188728) in the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Storage Disorders VCEP (PM5). There is a ClinVar entry for this variant (Variation ID 4029; 2 star review status) with seven laboratory submitters classifying the variant as 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_Very Strong, PM5, PS3_Moderate, PP4_Moderate, PP3.(Classification approved on August 17, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116610/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:15 O:1
• Conservation: PhyloP100: 0.998
• Publications: 97 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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 9 ACMG points.

• PS3: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.1935C>A	p.Asp645Glu	missense	Exon 14 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1935C>A	p.Asp645Glu	missense	Exon 15 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1935C>A	p.Asp645Glu	missense	Exon 14 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1935C>A	p.Asp645Glu	missense	Exon 14 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1935C>A	p.Asp645Glu	missense	Exon 15 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1950C>A	p.Asp650Glu	missense	Exon 14 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

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

GnomAD2 exomes AF: 0.000115 AC: 28 AN: 242876 AF XY: 0.000106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00155

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1458426 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 725200

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.000555 AC: 22 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 85566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110930

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

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41450

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000457 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000124 AC: 15

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
10	-	-	Glycogen storage disease, type II (11)
3	-	-	not provided (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	GAA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.52
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		1.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		1.0		Loss of stability (P = 0.287)
MVP		1.0
MPC		0.53
ClinPred		0.96	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.95
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28940868; hg19: chr17-78086721;