chr17-80110725-A-G

Variant names:

• chr17-80110725-A-G
• rs1555600730
• NM_000152.5:c.1438-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP4 PM3 PM2 PVS1

This summary comes from the ClinGen Evidence Repository: The c.1438-2A>G variant alters the canonical acceptor splice site of intron 9 and has been shown by RT-PCR to causing skipping of exon 10, resulting in an in frame deletion that removes about 4% of the gene product (PMID 24158270). Exon 10 forms part of the GAA catalytic barrel, including two residues, Trp481 and Trp516, which are part of the GAA active site (PMIDs 1856189; 22253258; DOI 10.1101/212837). Therefore, loss of this exon is expected to abolish GAA activity, and PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant has been reported in two individuals with Pompe disease who meet the ClinGen LSD VCEP’s specifications for PP4, and who are compound heterozygotes for this variant and a second pathogenic variant, c.-32-13T>G in one case (PMIDs 24158270), and c.955+1G>A in the other (PMID 29422078), meeting PM3. Other variants altering the same canonical splice site, c.1438-1G>T (PMID 18425781) and c.1438-1G>C (PMIDs 22538254, 24495340), have been reported in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 526521) with one submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401366755/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 8.76
• Publications: 1 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 13 ACMG points.

• PVS1: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.1438-2A>G		splice_acceptor intron	N/A	NP_000143.2
	GAA	NM_001079803.3		c.1438-2A>G		splice_acceptor intron	N/A	NP_001073271.1
	GAA	NM_001079804.3		c.1438-2A>G		splice_acceptor intron	N/A	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1438-2A>G		splice_acceptor intron	N/A	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.1438-2A>G		splice_acceptor intron	N/A	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.1438-2A>G		splice_acceptor intron	N/A	ENSP00000460543.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461322 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 726988

African (AFR) AF: 0.00 AC: 0 AN: 33474

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111768

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:4

Apr 21, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Mar 30, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1438-2A>G variant alters the canonical acceptor splice site of intron 9 and has been shown by RT-PCR to causing skipping of exon 10, resulting in an in frame deletion that removes about 4% of the gene product (PMID 24158270). Exon 10 forms part of the GAA catalytic barrel, including two residues, Trp481 and Trp516, which are part of the GAA active site (PMIDs 1856189; 22253258; DOI 10.1101/212837). Therefore, loss of this exon is expected to abolish GAA activity, and PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant has been reported in two individuals with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4, and who are compound heterozygotes for this variant and a second pathogenic variant, c.-32-13T>G in one case (PMIDs 24158270), and c.955+1G>A in the other (PMID 29422078), meeting PM3. Other variants altering the same canonical splice site, c.1438-1G>T (PMID 18425781) and c.1438-1G>C (PMIDs 22538254, 24495340), have been reported in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 526521) with one submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4.

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 9 of the GAA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with late onset glycogen storage disease type II (PMID: 24158270). ClinVar contains an entry for this variant (Variation ID: 526521). Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 24158270). For these reasons, this variant has been classified as Pathogenic.

Aug 03, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		8.8
GERP RS		5.3
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.47		Position offset: 48
DS_AL_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs1555600730; hg19: chr17-78084524;