rs1057516924

Variant names:

• chr17-80117059-G-AT
• rs1057516924
• NM_000152.5:c.2281delGinsAT

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: c.2281delinsAT (p.Ala761IlefsTer35) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 3 patients with Pompe disease including one individual with documentation of laboratory values showing GAA deficiency, meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate (PMID 17056254), and another stated to have deficient GAA activity (laboratory values not available) and on enzyme replacement therapy, meeting PP4 (PMID 29181627)(PP4_Moderate was applied). Both of these patients are compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (2 x 0.5 points = 1 point, PM3). Another patient was identified by newborn screening and was compound heterozygous for the variant, c.2238G>C (p.Trp746Cys), and a pseudodeficiency variant, c.2065G>A (PMID 33202836). This data may be used in the assessment of p.Trp746Cys and was not included here to avoid circular logic. The c.2281delinsAT variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 370993, 2 star review status) with one submitter classifying 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 specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041905/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 frameshift, missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 0.410
• Publications: 1 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

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.2281delGinsAT	p.Ala761IlefsTer35	frameshift missense	Exon 16 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2281delGinsAT	p.Ala761IlefsTer35	frameshift missense	Exon 17 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2281delGinsAT	p.Ala761IlefsTer35	frameshift missense	Exon 16 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.2281delGinsAT	p.Ala761IlefsTer35	frameshift missense	Exon 16 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2281delGinsAT	p.Ala761IlefsTer35	frameshift missense	Exon 17 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2296delGinsAT	p.Ala766IlefsTer35	frameshift missense	Exon 16 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Glycogen storage disease, type II (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.41
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs1057516924; hg19: chr17-78090858;