17-80110841-G-C

Variant names:

• chr17-80110841-G-C
• rs770780848
• NM_000152.5:c.1551+1G>C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4_Moderate PVS1 PM3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1551+1G>C variant alters the canonical donor splice site of intron 10 of GAA. Sequence analysis of cDNA from an individual who is compound heterozygous for this variant revealed that the variant results in skipping of exon 10 (GAA has 20 exons). Skipping of exon 10 results in an in-frame deletion of amino acids 480-517. This region forms part of the GAA catalytic barrel (amino acids 347-727) including two residues, Trp481 and Trp516, which are important in active site architecture and substrate binding (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837; Roig-Zamboni et al, 2017, PMID:29061980). Therefore, loss of this exon is expected to abolish GAA activity (PVS1). At least 7 patients with findings consistent with Pompe disease have been reported with this variant. GAA activity was reported for 2 patients and was deficient (<10% residual activity) (PMID:7881425, 25673129) (PP4_Moderate). At least 5 patients are compound heterozygous for the variant and c.-32-13T>G (known pathogenic variant) (ClinVar Variation ID: 4027) (phase unknown, max 2 x 0.5 points) (PMID:7881425, 16917947, 25673129). Two patients are compound heterozygous for the variant and another variant in GAA, either c.1437+2T>C (PMID:11343339) or c.1755-1G>A (PMID:17056254); both confirmed in trans. The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. 1 point (PM3). This variant is absent in gnomAD v2.1.1. In gnomAD v4.1.0., the highest population minor allele frequency is 0.000001695 (2/1179958 alleles; 0 homozygotes) which is lower that the ClinGen LD VCEP's threshold for PM2_Supporting (<0.001), in the European non-Finnish population, meeting this criterion (PM2_Supporting). Other variants at the same canonical donor splice site have been reported in patients with Pompe disease, including c.1551+1G>A, c.1551+1G>T, and c.1551+2T>G (www.pompevariantdatabase.nl). These variants have not yet been classified by the ClinGen LD VCEP. There is a ClinVar entry for this variant (Variation ID: 554983). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 4, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA401367167/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 9.39

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]

ACMG classification

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1551+1G>C		splice_donor_variant, intron_variant	Intron 10 of 19	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1551+1G>C		splice_donor_variant, intron_variant	Intron 10 of 19	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461748 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5

Dec 10, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.1551+1G>C variant alters the canonical donor splice site of intron 10 of GAA. Sequence analysis of cDNA from an individual who is compound heterozygous for this variant revealed that the variant results in skipping of exon 10 (GAA has 20 exons). Skipping of exon 10 results in an in-frame deletion of amino acids 480-517. This region forms part of the GAA catalytic barrel (amino acids 347-727) including two residues, Trp481 and Trp516, which are important in active site architecture and substrate binding (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837; Roig-Zamboni et al, 2017, PMID: 29061980). Therefore, loss of this exon is expected to abolish GAA activity (PVS1). At least 7 patients with findings consistent with Pompe disease have been reported with this variant. GAA activity was reported for 2 patients and was deficient (<10% residual activity) (PMID: 7881425, 25673129) (PP4_Moderate). At least 5 patients are compound heterozygous for the variant and c.-32-13T>G (known pathogenic variant) (ClinVar Variation ID: 4027) (phase unknown, max 2 x 0.5 points) (PMID: 7881425, 16917947, 25673129). Two patients are compound heterozygous for the variant and another variant in GAA, either c.1437+2T>C (PMID: 11343339) or c.1755-1G>A (PMID: 17056254); both confirmed in trans. The allelic data from these patients will be used in the assessment of the second variant and is not included here to avoid circular logic. 1 point (PM3). This variant is absent in gnomAD v2.1.1. In gnomAD v4.1.0., the highest population minor allele frequency is 0.000001695 (2/1179958 alleles; 0 homozygotes) which is lower that the ClinGen LD VCEP's threshold for PM2_Supporting (<0.001), in the European non-Finnish population, meeting this criterion (PM2_Supporting). Other variants at the same canonical donor splice site have been reported in patients with Pompe disease, including c.1551+1G>A, c.1551+1G>T, and c.1551+2T>G (www.pompevariantdatabase.nl). These variants have not yet been classified by the ClinGen LD VCEP. There is a ClinVar entry for this variant (Variation ID: 554983). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 4, 2024) -

Nov 10, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 10 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 Pompe disease (PMID: 7881425, 22252923, 33202836). This variant is also known as IVS10 +1GT-CT. ClinVar contains an entry for this variant (Variation ID: 554983). 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: 7881425). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Dec 21, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -25
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs770780848; hg19: chr17-78084640;