chr17-80105132-G-T

Position:

• chr17-80105132-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2_Supporting PS3 PM3_Strong PP4_Moderate PP3

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

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 12 ACMG points.

• PS3: 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.
• PP3: 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/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.546G>T	p.Thr182Thr	splice_region_variant, synonymous_variant	2/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.546G>T	p.Thr182Thr	splice_region_variant, synonymous_variant	2/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33

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: 11 AN: 1451668 Hom.: 0 Cov.: 36 AF XY: 0.00000416 AC XY: 3 AN XY: 721552

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: 1 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

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

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 02, 2023	- -
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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

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	19
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

Other links and lift over

dbSNP: rs143523371; hg19: chr17-78078931;