17-80104542-T-G

Variant names:

• chr17-80104542-T-G
• rs386834236
• NM_000152.5:c.-32-13T>G

Variant summary

Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3 PVS1_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.-32-13T>G variant occurs in the acceptor splice site region of intron 1 of GAA and results in a reduced level of normally spliced GAA transcripts (“leaky splicing”) allowing for the production of residual GAA activity. This variant, historically termed IVS1-13T>G and -45T>G, is the most common GAA variant identified in patients with late-onset Pompe disease; about 36-90% of individuals with late-onset Pompe disease are heterozygous for this variant (PMID:20301438, 31342611). Haplotype analysis suggests that c.-32-13T>G has arisen at least twice (PMID:17210890).RT-PCR analysis of fibroblast RNA from patients with the variant, in addition to minigene studies assessing the splicing impact of c.-32-13T>G, have identified various aberrantly spliced transcripts as well as a low level of the normal transcript. The aberrant splice variants include SV1, which retains the first 36 nt of intron 1 and lacks exon 2; SV2, in which exon 2 is completely spliced out; and SV3, in which exon 2 is partially spliced out. The same aberrant splicing variants, missing all or part of exon 2, have also been found at low levels in the RNA of unaffected individuals and when the normal GAA sequence is analyzed in minigene studies (PMID:7717400, 8817337, 17210890, 24150945). Overall, the variant appears to reduce the level of normal GAA transcripts to about 10-20% of wild type. This “leaky splicing” allows for some active GAA enzyme to be produced, thereby delaying onset of symptoms in individuals who carry this variant. It should be noted that these in vitro observations pertain to data collected in non muscle cell lines, the precise effect that this variant may have in vivo within muscle is not known. In cells from patients and cells transfected with the variant, antisense oligonucleotides and other treatments have been shown to increase the level of exon 2 inclusion, producing correctly spliced transcripts; to increase the residual activity of GAA; and to reduce the level of glycogen (PMID:24150945, 28624228, 28629821, 31301153, 32317649, 33426149, 36401034). Based on the accumulation of evidence, PVS1 is applied at strong (PMID:37352859).Hundreds of patients with this variant have been reported in the literature (see list of publications in https://www.pompevariantdatabase.nl/ ). There are numerous of examples of affected patients who are heterozygous for c.-32-13T>G and another variant in GAA that has been classified as pathogenic by the ClinGen LD GCEP (pathogenic classification does not require use of c.-32-13T>G for PM3). To provide some examples, the variant has been found in compound heterozygosity with c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (4 probands; max 2 x 0.5 points) (PMID:27189384), c.1051delG (ClinVar Variation ID: 188841, SCV001371764.1) (0.5 points) (PMID:27189384), c.2481+102_2646+31del (ClinVar Variation ID: 657307) (0.5 points) (PMID:27189384), c.2331+2T>A (ClinGen Variation ID: 371281) (2 probands) (2 x 0.5 points) (PMID:27189384), c.1548G>A (p.Trp516Ter) (ClinVar Variation ID: 189025, SCV001371740.1) (0.5 points) (PMID:27189384), c.1441T>C (p.Trp481Arg) (ClinVar Variation ID: 189007, SCV004227917.1) (0.5 points) (PMID:27189384), c.1551+1G>C (ClinVar Variation ID: 554983) (0.5 points) (PMID:7881425), c.784G>A (p.Glu262Lys) (ClinVar Variation ID: 188806, SCV002032128.1) (0.5 points) (PMID:25673129), and c.670C>T (p.Arg224Trp) (Variation ID: 189188, SCV001371775.1) (0.5 points) (PMID:25673129), as well as homozygous individuals (max 2 x 0.5 points) (PMID:25673129, 26231297 34405923). >7 points (PM3_VeryStrong).While the variant has never been associated with classical infantile-onset Pompe disease, the age of onset and severity of disease in patients with the variant can vary widely, even in individuals who are compound heterozygous for c.-32-13T>G and a complete loss of function variant (PMID:17210890, 34405923). Clinically affected patients who are homozygous for the variant have also been reported. However, some homozygous individuals appear to remain asymptomatic, leading to discussions on how best to follow these individuals if identified on newborn screen (PMID:30922962). Studies indicate that one of the factors that can modify the phenotype is the presence of another variant, c.510C>T, in cis with c.-32-13T>G. This variant has been shown to further reduce the level of normal GAA mRNA causing early onset and greater severity of symptoms (PMID:30922962).The highest minor allele frequency (MAF) in gnomAD v2.1.1. is 0.005293 (614/116004 alleles) in the European non-Finnish population, with one homozygote in the “remaining individuals” group. In gnomAD v4.1.0, the highest population MAF is 0.006355 (7335/1154180 alleles; 19 homozygotes) in the European non-Finnish population. Although this allele frequency meets the BS1 threshold suggested by the LD VCEP, the fact that this variant is the most common variant in individuals with late onset Pompe disease accounts for the population based allele frequency that is observed. Therefore, BS1 was not applied. In addition there is abundant evidence to support its pathogenicity.Other variants in the same splice region have been identified in patients with Pompe disease including c.-32-3C>G, c.-32-3C>A, c.-32-2A>G, and c.-32-1G>C (PMID:31301153, 33560568). The classification of c.-32-13T>G will be used to support the classification of these other variants. Therefore, to avoid circular logic, their classification was not used in the classification of c.-32-13T>G. There is a ClinVar entry for this variant (Variation ID: 4027).In summary, the c.-32-13T>G variant (also known as IVS1-13T>G) meets the criteria to be classified as pathogenic for Pompe disease. It results in residual GAA activity and is the most common GAA variant causing late-onset Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 2.0): PVS1_Strong, PM3_Very Strong, PP4_Moderate.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1st, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA116606/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (23 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Pathogenic reviewed by expert panel P:58 O:2
• Conservation: PhyloP100: -0.419
• Publications: 222 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 8 ACMG points.

• PVS1: 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.-32-13T>G		intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.-32-13T>G		intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.-32-13T>G		intron	N/A	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.-32-13T>G		intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.-32-13T>G		intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000945488.1		c.-45T>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 20	ENSP00000615547.1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00344 AC: 759 AN: 220344 AF XY: 0.00373

Gnomad AFR exome AF: 0.000880

Gnomad AMR exome AF: 0.00274

Gnomad ASJ exome AF: 0.00523

Gnomad EAS exome AF: 0.000225

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.00530

Gnomad OTH exome AF: 0.00527

GnomAD4 exome AF: 0.00542 AC: 7665 AN: 1415278 Hom.: 23 Cov.: 29 AF XY: 0.00545 AC XY: 3810 AN XY: 699350

African (AFR) AF: 0.000674 AC: 22 AN: 32640

American (AMR) AF: 0.00267 AC: 111 AN: 41616

Ashkenazi Jewish (ASJ) AF: 0.00510 AC: 123 AN: 24102

East Asian (EAS) AF: 0.000128 AC: 5 AN: 39102

South Asian (SAS) AF: 0.00216 AC: 178 AN: 82314

European-Finnish (FIN) AF: 0.000281 AC: 13 AN: 46188

Middle Eastern (MID) AF: 0.00124 AC: 6 AN: 4846

European-Non Finnish (NFE) AF: 0.00641 AC: 6961 AN: 1086178

Other (OTH) AF: 0.00422 AC: 246 AN: 58292

GnomAD4 genome AF: 0.00376 AC: 572 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74442

African (AFR) AF: 0.00118 AC: 49 AN: 41550

American (AMR) AF: 0.00739 AC: 113 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00550 AC: 374 AN: 68002

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00466 Hom.: 3

Bravo AF: 0.00359

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
35	-	-	Glycogen storage disease, type II (37)
15	-	-	not provided (15)
2	-	-	Glycogen storage disease due to acid maltase deficiency, late-onset (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	GAA-related disorder (1)
1	-	-	Glycogen storage disease (1)
1	-	-	Glycogen storage disease, type IV (1)
1	-	-	Myopathy (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.62
PhyloP100		-0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs386834236; hg19: chr17-78078341;