17-80105132-G-T

Position:

chr17-80105132-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3PM2_SupportingPS3PM3_StrongPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.546C>T (p.Thr182=) variant in GAA is a synonymous (silent) variant that alters the last nucleotide of exon 2 and has been found to impact splicing of intron 2 (PMID 19609281, 21757382, 33168984). At least 20 patients with Pompe disease and this variant have been reported including 17 patients with documented laboratory values for GAA activity <10% of normal mean control level of GAA activity in leukocytes, <30% of normal mean control level of GAA activity in cultured fibroblasts or activity in the affected range in cultured skin fibroblasts, leukocytes, lymphocytes, or dried blood spot (PMID 19609281, 21982629, 25388776, 28433475, 29124014, 30093193); pseudodeficiency variants are confirmed absent in one of these patients (PMID 28433475)(PP4_Moderate). The patients typically have late onset Pompe disease and are of East Asian descent. Of these patients, two are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP, including c.118C>T (p.Arg40Ter) (PMID 29124014, ClinVar SCV SCV001371737.1), and c.1935C>A (p.Asp645Glu)(PMID 21757382), and seven patients are homozygous for the variant (PMID 20202878, 21982629, 29124014, 30093193). Additional patients are compound heterozygous for the variant and a missense variant - c.796C>T (p.Pro266Ser) (PMID 29124014), c.1099T>G (p.Trp367Gly) (PMID 29124014), c.1316T>A (p.Met439Lys)(PMID 28433475), p.Arg600Cys (PMID 19609281, 20202878, 21982629), c.2171C>A (p.Ala724Asp)(PMID 25388776), c.2481G>A (p.Gln827His) (PMID 29124014); the in trans data from these patients will be used in assessment of these variants and is not included here in order to avoid circular logic (PM3_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Results of RT-PCR and subsequent sequencing of cDNA from patient skin fibroblasts from multiple studies are consistent with c.546G>T being a leaky splice variant, with production of some normal transcript in addition to skipping of exon 2 and use of a cryptic splice site in intron 2 (PMID 19609281, 21757382, 33168984)(PS3). Consistent with this finding, the computational splicing predictor SpliceAI gives a score of 0.69 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA (PP3). Of note, additional variants at this position, c.546G>A (ClinVar Variation ID: 280955) and c.546G>C (ClinVar Variation ID: 281056), have also been reported in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 370637, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PS3, PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041884/MONDO:0009290/010

Frequency

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

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

GAA
NM_000152.5 splice_region, synonymous

Scores

Splicing: ADA: 0.9993

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 0.305

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS3

PM2

PM3

PP3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.546G>T	p.Thr182=	splice_region_variant, synonymous_variant	2/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.546G>T	p.Thr182=	splice_region_variant, synonymous_variant	2/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000758

AC:

AN:

1451668

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

721552

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000812

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 21, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 02, 2021	The NM_000152.5:c.546C>T (p.Thr182=) variant in GAA is a synonymous (silent) variant that alters the last nucleotide of exon 2 and has been found to impact splicing of intron 2 (PMID 19609281, 21757382, 33168984). At least 20 patients with Pompe disease and this variant have been reported including 17 patients with documented laboratory values for GAA activity <10% of normal mean control level of GAA activity in leukocytes, <30% of normal mean control level of GAA activity in cultured fibroblasts or activity in the affected range in cultured skin fibroblasts, leukocytes, lymphocytes, or dried blood spot (PMID 19609281, 21982629, 25388776, 28433475, 29124014, 30093193); pseudodeficiency variants are confirmed absent in one of these patients (PMID 28433475)(PP4_Moderate). The patients typically have late onset Pompe disease and are of East Asian descent. Of these patients, two are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LSD VCEP, including c.118C>T (p.Arg40Ter) (PMID 29124014, ClinVar SCV SCV001371737.1), and c.1935C>A (p.Asp645Glu)(PMID 21757382), and seven patients are homozygous for the variant (PMID 20202878, 21982629, 29124014, 30093193). Additional patients are compound heterozygous for the variant and a missense variant - c.796C>T (p.Pro266Ser) (PMID 29124014), c.1099T>G (p.Trp367Gly) (PMID 29124014), c.1316T>A (p.Met439Lys)(PMID 28433475), p.Arg600Cys (PMID 19609281, 20202878, 21982629), c.2171C>A (p.Ala724Asp)(PMID 25388776), c.2481G>A (p.Gln827His) (PMID 29124014); the in trans data from these patients will be used in assessment of these variants and is not included here in order to avoid circular logic (PM3_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Results of RT-PCR and subsequent sequencing of cDNA from patient skin fibroblasts from multiple studies are consistent with c.546G>T being a leaky splice variant, with production of some normal transcript in addition to skipping of exon 2 and use of a cryptic splice site in intron 2 (PMID 19609281, 21757382, 33168984)(PS3). Consistent with this finding, the computational splicing predictor SpliceAI gives a score of 0.69 for donor loss, predicting that the variant disrupts the donor splice site of intron 2 of GAA (PP3). Of note, additional variants at this position, c.546G>A (ClinVar Variation ID: 280955) and c.546G>C (ClinVar Variation ID: 281056), have also been reported in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID: 370637, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PS3, PM3_Strong, PP4_Moderate, PP3, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 25, 2023	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2, and is expected to result in the loss of the initiator methionine (PMID: 19609281, 31301153). Experimental studies have shown that this variant affects GAA function (PMID: 21982629). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 370637). This variant has been observed in individual(s) with adult onset Pompe disease (PMID: 19609281, 22196155, 30093193). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 182 of the GAA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAA protein. RNA analysis indicates that this variant induces altered splicing and is likely to result in the loss of the initiator methionine. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 02, 2023	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.70

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.70

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over