rs1555601780

Variant names:

• chr17-80113311-CTG-C
• rs1555601780
• NM_000152.5:c.2136_2137delGT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4 PM2_Supporting PM3_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2136_2137del (p.Phe713ProfsTer23) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 15/20, predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). A patient with this variant was reported to have deficient GAA activity and to be on enzyme replacement therapy for Pompe disease (PMID:25614309, 27896092)(PP4). This patient is compound heterozygous, phase unknown, for the variant and a pathogenic variant in GAA, c.-32-13T>G ( PMID:25614309, 27896092)(PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 556718; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Storage Disorders VCEP (Specification Version 2.0): PVS1, PM2_Supporting, PM3_Supporting, PP4.(Classification approved on August 17th, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA658795274/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 6.08
• Publications: 0 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 11 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.2136_2137delGT	p.Phe713ProfsTer23	frameshift	Exon 15 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2136_2137delGT	p.Phe713ProfsTer23	frameshift	Exon 16 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2136_2137delGT	p.Phe713ProfsTer23	frameshift	Exon 15 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.2136_2137delGT	p.Phe713ProfsTer23	frameshift	Exon 15 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2136_2137delGT	p.Phe713ProfsTer23	frameshift	Exon 16 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2151_2152delGT	p.Phe718ProfsTer23	frameshift	Exon 15 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447030 Hom.: 0 AF XY: 0.00000139 AC XY: 1 AN XY: 718462

African (AFR) AF: 0.00 AC: 0 AN: 33240

American (AMR) AF: 0.0000232 AC: 1 AN: 43062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25696

East Asian (EAS) AF: 0.00 AC: 0 AN: 38960

South Asian (SAS) AF: 0.00 AC: 0 AN: 83492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105098

Other (OTH) AF: 0.00 AC: 0 AN: 59774

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		6.1
Mutation Taster		=0/200	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: rs1555601780; hg19: chr17-78087110;