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, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.2706delG	p.Lys903ArgfsTer2	frameshift	Exon 19 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2706delG	p.Lys903ArgfsTer2	frameshift	Exon 20 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2706delG	p.Lys903ArgfsTer2	frameshift	Exon 19 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.2706delG	p.Lys903ArgfsTer2	frameshift	Exon 19 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2706delG	p.Lys903ArgfsTer2	frameshift	Exon 20 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2721delG	p.Lys908ArgfsTer2	frameshift	Exon 19 of 20	ENSP00000603465.1

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

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Glycogen storage disease, type II (5)

Computational scores

Source: dbNSFP v4.9

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;