rs143523371

Variant names:

• chr17-80105132-G-A
• rs143523371
• NM_000152.5:c.546G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80105132-G-A
• chr17-80105132-G-C
• chr17-80105132-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PVS1_Strong PS1_Moderate PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.546G>A variant alters that last nucleotide of exon 2 of GAA, but does not result in an amino acid change (p.Thr182=). Two different studies, one using real-time RT-PCR to analyze RNA from cultured fibroblasts from an patient with the variant, and another involving minigene analysis showed that the variant disrupts normal splicing, resulting in skipping of exon 2, with a low proportion of normal transcripts produced (PMID:14695532, 31301153). Exon 2 contains the start methionine and signal sequence for GAA (amino acids 1-27; https://www.uniprot.org/uniprot/P10253). In addition, deletion of exon 2 results in complete loss of enzyme activity when expressed in heterologous cells (PMID 7881425; PMID 7717400). As this variant appears to allow a low level of normal splicing to occur, PVS1 was applied at the strong level (PVS1_Strong). Four individuals with a diagnosis of late onset Pompe disease and this variant have been reported with documented laboratory values showing GAA activity in the affected range in dried blood spots or muscle, or <30% activity in skin fibroblasts or <10% activity in muscle and lymphocytes (PMID:14695532, 21484825, 21984055, 25037089) (PP4_Moderate). Two of these patients are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP including c.525delT (PMID:14695532), and c.655G>A (p.Gly219Arg) (PMID:25037089), phase not confirmed (PM3). Additional patients have been reported who are compound heterozygous for the variant and either c.736delC (PMID:30564623), c.307T>C (p.Cys103Arg) (PMID:21984055), c.2041-1G>A (PMID:21484825); 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. Finally, allelic data for newborn screening cases was not included here due to either lack of confirmation, lack of clinical symptoms in suspected LOPD patients, or presence of pseudodeficiency variants (PMID:33202836, 34995642). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 (2/19660 alleles) in the East Asian population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Other variants at the same nucleotide position (c.546G>T, c.546G>C), and in the same splice region (c.546+1G>T, c.546+2T>C, c.546+5G>T, and c.546del2‐5) have been reported in individuals with Pompe disease (https://www.pompevariantdatabase.nl/). All of these variants have been shown to result in skipping of exon 2 using a minigene assay (PMID:31301153). c.546G>T has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP (PS1_Moderate, PMID:37352859). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, based in the specification of the ClinGen Lysosomal Diseases VCEP: PVS1_Strong, PS1_Moderate, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on July 18, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814895/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: GAA NM_000152.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 0.305
• 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, 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS1: 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.
• 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.546G>A	p.Thr182Thr	splice_region synonymous	Exon 2 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.546G>A	p.Thr182Thr	splice_region synonymous	Exon 3 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.546G>A	p.Thr182Thr	splice_region synonymous	Exon 2 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.546G>A	p.Thr182Thr	splice_region synonymous	Exon 2 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.546G>A	p.Thr182Thr	splice_region synonymous	Exon 3 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.546G>A	p.Thr182Thr	splice_region synonymous	Exon 2 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152242 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: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000296 AC: 7 AN: 236410 AF XY: 0.00000769

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000282

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000916 AC: 133 AN: 1451670 Hom.: 0 Cov.: 36 AF XY: 0.0000887 AC XY: 64 AN XY: 721554

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39578

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.000115 AC: 127 AN: 1109026

Other (OTH) AF: 0.0000333 AC: 2 AN: 60144

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000491

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
12	-	-	Glycogen storage disease, type II (12)
3	-	-	not provided (3)
2	-	-	Glycogen storage disease (2)
1	-	-	GAA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Benign	0.91
PhyloP100		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.69		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143523371; hg19: chr17-78078931;