chr17-80113365-G-T

Variant names:

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

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

Selected	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
	GAA	NM_001079803.3		c.2188G>T	p.Glu730*	stop_gained splice_region	Exon 16 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.2188G>T	p.Glu730*	stop_gained splice_region	Exon 15 of 20	NP_001073272.1

Ensembl Transcripts

Selected	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
	GAA	ENST00000390015.7	TSL:1	c.2188G>T	p.Glu730*	stop_gained splice_region	Exon 16 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.2188G>T	p.Glu730*	stop_gained splice_region	Exon 15 of 20	ENSP00000460543.2

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

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3

Jun 29, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GAA c.2188G>T (p.Glu730X) variant results in a premature termination codon, predicted to cause a truncated or absent GAA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. If this nonsense variant results in a protein product, this variant is not predicted to truncate any known functional domains of Lysosomal alpha-glucosidase. However, two independent functional assays in COS-1 and HEK 293 T cells have shown that the activity of Glu730X is not significantly different from mock control (Ebrahim_JIMD_2012 and Pittis_Am J Med Genet A_2003). Neither of these studies confirmed protein expression via Western Blotting, thus it is uncertain if this variant results in a stable protein that is inactive, nonsense mediated decay, or an unstable protein. At least one frameshift variant downstream of this position has been classified as pathogenic by our laboratory (e.g. p.Lys849fsX38), and one in silico tool predicts a damaging outcome for this variant. Additionally, this variant was absent in 39208 control chromosomes, and was cited in compound heterozygous state in one patient in the literature with Infantile Onset Pompe Disease. Taken together, this variant is classified as Pathogenic.

Feb 14, 2020

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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.

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 495665). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 12923862, 28951071). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu730*) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).

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;