rs1555601828

Variant names:

• chr17-80113365-G-T
• rs1555601828
• NM_000152.5:c.2188G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-80113365-G-T
• chr17-80113365-G-A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP4 PM3 PM2 PVS1

This summary comes from the ClinGen Evidence Repository: This variant, c.2188G>T (p.Glu730Ter), is a nonsense variant that is predicted to result in nonsense-mediated decay and lack of gene product. This is supported by functional studies in HEK293T cells and COS-1 cells, which showed undetectable GAA activity (PMIDs 12923862, 21972175). This variant is absent in gnomAD v2.1.1. It has been reported in 3 patients with Pompe disease who meet the ClinGen LSD VCEP specifications for PP4; two are compound heterozygous for the variant and c.-31-13T>G (PMIDs 28196920, 28951071; phase unknown) and one is compound heterozygous for the variant and a frameshift variant, c.829_851del, confirmed in trans (PMID 12923862), meeting PM3. There is a ClinVar entry for this variant (Variation ID: 495665, one star review status) with one submitter classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe Disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401370663/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GAA NM_000152.5 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9809
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.45
• 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

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.2188G>T	p.Glu730*	stop_gained splice_region	Exon 15 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2188G>T	p.Glu730*	stop_gained splice_region	Exon 16 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2188G>T	p.Glu730*	stop_gained splice_region	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.2188G>T	p.Glu730*	stop_gained splice_region	Exon 15 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2188G>T	p.Glu730*	stop_gained splice_region	Exon 16 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2203G>T	p.Glu735*	stop_gained splice_region	Exon 15 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422028 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 702856

African (AFR) AF: 0.00 AC: 0 AN: 32850

American (AMR) AF: 0.00 AC: 0 AN: 40438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24916

East Asian (EAS) AF: 0.00 AC: 0 AN: 37944

South Asian (SAS) AF: 0.00 AC: 0 AN: 81230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090036

Other (OTH) AF: 0.00 AC: 0 AN: 58622

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Glycogen storage disease, type II (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	54
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.4
Vest4		0.98
GERP RS		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.080		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: rs1555601828; hg19: chr17-78087164;