17-80104587-A-T

Variant names:

• chr17-80104587-A-T
• rs786204467
• NM_000152.5:c.1A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP4 PM2_Supporting PVS1_Strong PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1A>T (p.Met1?) variant in GAA may cause a truncated or absent protein by altering the start codon of the coding sequence. The next in-frame methionine is at position 122; if used, the gene product would be missing the signal sequence (PMID 22252923). When expressed in HEK293T cells, a very low level of an approximately 85 kD protein was seen on Western blot, suggesting the use of a downstream ATG in this in vitro system but there was no detectable GAA activity in the cells (PMID 22644586). There is also evidence that this variant may result in skipping of exon 2 in about 40-50% of transcripts when compared to wild type (PMID:31301153). Based on the specifications of the ClinGen LD VCEP, PVS1_Strong was applied. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). The variant has been reported in a patient with clinical features consistent with late onset Pompe disease on enzyme replacement therapy (PP4). This patient is compound heterozygous, phase unconfirmed, for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.-32-13T>G (ClinVar Variation ID: 4027) (PMID 27711114, 30022036) (PP4, PM3_Supporting). Of note, additional initiator codon variants, including c.1A>G, c.2T>C, and c.3G>A, have been reported in patients with Pompe disease (see http://www.pompevariantdatabase.nl/). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1_Strong, PP4, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 17, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA401359799/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 32)
• Consequence: GAA NM_000152.5 initiator_codon
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 1.38
• Publications: 26 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: Likely_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.1A>T	p.Met1?	initiator_codon	Exon 2 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1A>T	p.Met1?	initiator_codon	Exon 3 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1A>T	p.Met1?	initiator_codon	Exon 2 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.1A>T	p.Met1?	initiator_codon	Exon 2 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 3 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1A>T	p.Met1?	initiator_codon	Exon 2 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Glycogen storage disease, type II (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	14
DANN	Benign	0.78
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.26	T
PhyloP100		1.4
PROVEAN	Benign	-0.19	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.035	B
Vest4		0.67
MutPred		1.0		Loss of catalytic residue at M1 (P = 0.2704)
MVP		0.91
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.83
gMVP		0.50
Mutation Taster		=5/195	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: rs786204467; hg19: chr17-78078386;