17-80105137-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2_SupportingPVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.546+5G>T variant occurs in the donor splice region of intron 2 of GAA. RT-PCR of RNA from primary fibroblasts a patient who is compound heterozygous for c.[546+5G>T; 1726G>A] and c.1080C>G (p.Tyr360Ter) revealed a normal-sized fragment containing 2 sequences (one normal and one with a 3-bp insertion) and an aberrantly short fragment containing a deletion of exon 2 (PMID:34995642, Fig 6). Another study, using minigene analysis, showed that the variant results in almost complete skipping of exon 2 (PMID:31301153, Fig 3e, f). Consistent with this evidence, the computational predictor SpliceAI predicts loss of the donor splice site (score of 0.42) and gain of a splice donor 3bp downstream of the normal splice donor (score of 0.64). Any transcripts in which exon 2 is skipped would be missing the start codon and signal sequence (https://www.uniprot.org/uniprotkb/P10253/entry). This variant has been found in multiple individuals identified by newborn screening programs in Taiwan and Japan (PMID:20080426, 21232767, 31076647, 34995642). However, the variant always occurs in cis with pseudodeficiency variants (including c.1726G>A) which could be responsible for the reduced GAA activity observed in these individuals. One patient, who was compound heterozygous for the variant and c.1080C>G (p.Tyr360Ter), was reported to have initial CK elevation, and hypotonia for the first few years of life, but was later described as "normal" by the family at age 13 years (PMID:34995642). Therefore, despite the functional and predictive evidence indicating that this variant impacts splicing, the clinical significance of the variant is unclear. There has been no report of a patient with this variant who is clearly symptomatic for Pompe disease and, therefore, it is unknown if this variant may contribute to late-onset symptoms (neither PP4 nor PM3 were applied). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004978 in the East Asian population which is lower than ClinGen LD VCEP threshold of <0.001 (PM2_supporting). Other variants in the same donor splice site region have various classifications. For example, c.546+5G>A classified by the ClinGen LD VCEP as a variant of uncertain significance (ClinVar SCV004227903.1). Multiple other variants have been reported as pathogenic/likely pathogenic by ClinVar submitters (but not yet classified by the ClinGen LD VCEP) including c.546+2T>C, and c.546+2_+5del, and others in the same region have been classified in ClinVar as benign/Likely benign (not yet classified by the ClinGen LD VCEP) including c.546+4G>C; or VUS (c.546+3G>A). There is ClinVar entry for this variant (Variation ID: 557811). In summary, this variant has been classified as a variant of uncertain significance for Pompe disease by the ClinGen Lysosomal Disorders Variant Curation Expert Panel. Additional data, such as a report of a patient with clear symptoms of Pompe disease, or functional studies in muscle tissue, would be helpful. GAA-Specific ACMG-AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 2.0): PVS1_Strong, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 5, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8814901/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

GAA
ENST00000302262.8 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance reviewed by expert panel P:6U:4

Conservation

PhyloP100: 7.26

Publications

6 publications found

Variant links:

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

GAA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000302262.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GAA	NM_000152.5	MANE Select	c.546+5G>T	splice_region intron	N/A	NP_000143.2
GAA	NM_001079803.3		c.546+5G>T	splice_region intron	N/A	NP_001073271.1
GAA	NM_001079804.3		c.546+5G>T	splice_region intron	N/A	NP_001073272.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GAA	ENST00000302262.8	TSL:1 MANE Select	c.546+5G>T	splice_region intron	N/A	ENSP00000305692.3
GAA	ENST00000390015.7	TSL:1	c.546+5G>T	splice_region intron	N/A	ENSP00000374665.3
GAA	ENST00000714061.1		n.551G>T	non_coding_transcript_exon	Exon 3 of 21	ENSP00000519351.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000382

AC:

AN:

235344

AF XY:

0.0000309

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000498

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000828

AC:

AN:

1450136

Hom.:

Cov.:

AF XY:

0.00000833

AC XY:

AN XY:

720654

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.00

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.000228

AC:

AN:

39554

South Asian (SAS)

AF:

0.00

AC:

AN:

86186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1108494

Other (OTH)

AF:

0.00

AC:

AN:

60098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000585

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycogen storage disease, type II (9)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Benign

0.96

PhyloP100

7.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.64

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.64

Position offset: -2

DS_DL_spliceai

0.43

Position offset: -5

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over