rs763359208

Variant names:

• chr17-80119283-CTG-C
• rs763359208
• NM_000152.5:c.2815_2816delGT

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PM3 PM2_Supporting PVS1_Moderate PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.2815_2816del (p.Val939LeufsTer78) variant in GAA is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. The frameshift begins at amino acid 939; the normal GAA gene product is 952 amino acids in length. Hence <10% of the normal product is missing. The impact of adding an abnormal sequence of 78 amino acids to the C terminus of GAA, due to the frameshift, is unknown (PVS1_Moderate). At least 10 probands with this variant who have been diagnosed with Pompe disease have been described including 4 probands for whom residual GAA activity was provided and was either <1% normal in cultured skin fibroblasts (PMID 22538254) or below the normal range in dried blood spots (PMID:37542277, https://doi.org/10.3390/metabo11070446). Two of these probands and at least 2 additional patients were on enzyme replacement therapy (PMID 22538254, 25316892, 32373469, https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf) (PP4_Moderate). Patients reported with this variant include compound heterozygotes for the variant and another pathogenic/likely pathogenic variant in GAA, phase unknown, including for c.118C>T (p.Arg40Ter) (ClinVar SCV001371737.1) (PMID 24269976, 0.5 points), c.1935C>A (p.Asp645Glu) (ClinVar SCV002032138.1) (PMIDs 22538254, 28394184, 32373469, at least two patients, 2 x 0.5 points), c.2238G>C (p.Trp746Cys) (ClinVar SCV002032122.1) (PMIDs: 25316892, 34647686, 0.5 points), c.1082C>T (p.Pro361Leu) (ClinVar SCV002540670.1) (PMID:37542277, 0.5 points), and c.1843G>A (p.Gly615Arg) (ClinVar SCV002583372.1) (PMID:37542277, 0.25 points) and c.2585delG (PMID 28394184, 0.25 points); and confirmed in trans with c.2238G>C (p.Trp746Cys) https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf, 1 point). Total 4 points for PM3 (PM3_VeryStrong). Another patient has been reported as compound heterozygous for the variant and c.266G>T (p.Arg89Leu) (https://doi.org/10.3390/metabo11070446). The in trans data from this patient will be used for the assessment of p.Arg89Leu and is not included here in order to avoid circular logic. For another patient described with Pompe disease and the variant, a second variant was not identified (PMID 10338092). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001631 (3/18388; no homozygotes), and in gnomAD v4.1.0. it is 0.00006684 (3/44884; no homozygotes) in the East Asian population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 371481). 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 Lysosomal Diseases Variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PM3_VeryStrong, PVS1_Moderate, PP4_Moderate, PM2_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on November 22, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815886/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8 U:1
• Conservation: PhyloP100: 0.766
• 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 7 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.2815_2816delGT	p.Val939LeufsTer78	frameshift	Exon 20 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2815_2816delGT	p.Val939LeufsTer78	frameshift	Exon 21 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2815_2816delGT	p.Val939LeufsTer78	frameshift	Exon 20 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.2815_2816delGT	p.Val939LeufsTer78	frameshift	Exon 20 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2815_2816delGT	p.Val939LeufsTer78	frameshift	Exon 21 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2830_2831delGT	p.Val944LeufsTer78	frameshift	Exon 20 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251298 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461778 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	1	-	Glycogen storage disease, type II (8)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.77
Mutation Taster		=12/188	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs763359208; hg19: chr17-78093082;