rs1428358278

Variant names:

• chr17-80118711-AG-A
• rs1428358278
• NM_000152.5:c.2706delG

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000152.5(GAA):c.2706del variant in GAA is a frameshift variant predicted to cause a premature stop codon (p.Lys903ArgfsTer2). Although the predicted termination codon occurs in the penultimate exon, it is more than 50 base pairs upstream from the 3' end of the exon, and therefore, predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is supported by the finding of a patient with this variant who has no GAA cross reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (PMID 22252923) (PVS1). Three patients have been reported with deficient GAA activity in either dried blood spots (in the affected range based on clinical laboratory data) or cultured fibroblasts (<1% normal activity) (personal communication, PMIDs 22252923, 31710733) (PP4_Moderate). One of these patients is compound heterozygous, phase unknown, for the variant and a pathogenic variant in GAA, c.-33-13T>G ( PMID:31710733), and another is homozygous for the variant (PMID:22252923, personal communication) (PM3). A patient is compound heterozygous for c.2706del and c.2051C>T (p.Pro684Leu). The alleic data from this patient will be used in the classification of p.Pro684Leu and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 554339, 2 star review status) with 2 submitters reporting the variant as pathogenic and one as likely pathogenic). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specific by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658795297/MONDO:0009290/010

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 0.293
• Publications: 2 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.2706delG	p.Lys903ArgfsTer2	frameshift_variant	Exon 19 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2706delG	p.Lys903ArgfsTer2	frameshift_variant	Exon 19 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

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 Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

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:5

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5

Sep 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys903Argfs*2) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 22252923). ClinVar contains an entry for this variant (Variation ID: 554339). 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. -

Sep 06, 2022

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5(GAA):c.2706del variant in GAA is a frameshift variant predicted to cause a premature stop codon (p.Lys903ArgfsTer2). Although the predicted termination codon occurs in the penultimate exon, it is more than 50 base pairs upstream from the 3' end of the exon, and therefore, predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is supported by the finding of a patient with this variant who has no GAA cross reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (PMID 22252923) (PVS1). Three patients have been reported with deficient GAA activity in either dried blood spots (in the affected range based on clinical laboratory data) or cultured fibroblasts (<1% normal activity) (personal communication, PMIDs 22252923, 31710733) (PP4_Moderate). One of these patients is compound heterozygous, phase unknown, for the variant and a pathogenic variant in GAA, c.-33-13T>G ( PMID: 31710733), and another is homozygous for the variant (PMID: 22252923, personal communication) (PM3). A patient is compound heterozygous for c.2706del and c.2051C>T (p.Pro684Leu). The alleic data from this patient will be used in the classification of p.Pro684Leu and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 554339, 2 star review status) with 2 submitters reporting the variant as pathogenic and one as likely pathogenic). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG-AMP criteria met, as specific by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. -

Oct 16, 2017

Counsyl

Significance: Likely 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. -

Mar 09, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAA c.2706delG (p.Lys903ArgfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by HGMD. The variant was absent in 250632 control chromosomes (gnomAD). c.2706delG has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example: Bali_2012, Khan_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic(n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29
Mutation Taster		=11/189	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -38

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

Other links and lift over

dbSNP: rs1428358278; hg19: chr17-78092510;