rs1057517148

Variant names:

• chr17-80117111-T-A
• rs1057517148
• NM_000152.5:c.2331+2T>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80117111-T-A
• chr17-80117111-T-C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2_Supporting PM3 PP4_Moderate PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2331+2T>A variant in GAA occurs within the canonical splice donor site of intron 16. RT-PCR of RNA from cultured fibroblasts from a patient who is compound heterozygous for this variant revealed that c.2331+2T>A leads to use of an alternative splice donor at c.2315, resulting in a frameshift, premature stop codon and nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID 33168984). Western blot of protein from cultured fibroblasts from another patient with this variant found absence of cross-reactive immunological material for GAA supporting that this variant results in lack of gene product (PMID 22252923)(PVS1). At least 5 patients with Pompe disease have been reported with this variant including 4 patients with documented GAA deficiency (PMID 26693141, 27189384, 32071926)(PP4_Moderate). Of these patients, three are compound heterozygous for the variant and c.-32-13T>G, with one confirmed in trans (PMIDs 27189384, 30922962, 29149851), one is compound heterozygous for the variant and c.1327-61_1437+171del, phase unknown (PMID 32071926), and one patient is homozygous (PMID 26693141)(PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in the European non-Finnish population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.97 for donor loss, predicting that the variant disrupts the donor splice site of intron 16 of GAA. But since PVS1 is applied, PP3 cannot be applied at the same time. There is a ClinVar entry for this variant (Variation ID: 371281, 2 star review status) with seven submitters classifying the variant as 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 Diseases VCEP (ACMG/AMP specifications version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041906/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 4.56
• Publications: 6 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.2331+2T>A		splice_donor_variant, intron_variant	Intron 16 of 19	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2331+2T>A		splice_donor_variant, intron_variant	Intron 16 of 19	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 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

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247930 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460076 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726364

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5

Dec 19, 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.2331+2T>A variant in GAA occurs within the canonical splice donor site of intron 16. RT-PCR of RNA from cultured fibroblasts from a patient who is compound heterozygous for this variant revealed that c.2331+2T>A leads to use of an alternative splice donor at c.2315, resulting in a frameshift, premature stop codon and nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID 33168984). Western blot of protein from cultured fibroblasts from another patient with this variant found absence of cross-reactive immunological material for GAA supporting that this variant results in lack of gene product (PMID 22252923)(PVS1). At least 5 patients with Pompe disease have been reported with this variant including 4 patients with documented GAA deficiency (PMID 26693141, 27189384, 32071926)(PP4_Moderate). Of these patients, three are compound heterozygous for the variant and c.-32-13T>G, with one confirmed in trans (PMIDs 27189384, 30922962, 29149851), one is compound heterozygous for the variant and c.1327-61_1437+171del, phase unknown (PMID 32071926), and one patient is homozygous (PMID 26693141)(PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 in the European non-Finnish population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.97 for donor loss, predicting that the variant disrupts the donor splice site of intron 16 of GAA. But since PVS1 is applied, PP3 cannot be applied at the same time. There is a ClinVar entry for this variant (Variation ID: 371281, 2 star review status) with seven submitters classifying the variant as 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 Diseases VCEP (ACMG/AMP specifications version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 19, 2024) -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The c.2331+2T>A variant in GAA has been reported in at least 4 individuals (including 1 Belgian individual) with Glycogen Storage Disease II (PMID: 22252923, 18425781, 20817528), and has also been reported pathogenic by Counsyl in ClinVar (Variation ID: 371281). This variant has been identified in 0.001% (1/111712) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057517148). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II slightly increases the likelihood that the c.2331+2T>A variant is pathogenic (PMID: 20817528). The phenotype of an individual heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in their fibroblasts (PMID: 20817528). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and an occurrence with a pathogenic GAA variant in an individual with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, PM2, PP4 (Richards 2015). -

May 13, 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 16 of the GAA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Pompe disease (PMID: 31086307, 32071926). ClinVar contains an entry for this variant (Variation ID: 371281). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Aug 18, 2016

Counsyl

Significance: 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. -

Feb 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 15, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		4.6
GERP RS		4.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.51		Position offset: -18
DS_DL_spliceai		0.97		Position offset: -2

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

Other links and lift over

dbSNP: rs1057517148; hg19: chr17-78090910;