17-80104587-A-T

Position:

• chr17-80104587-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_Supporting PVS1_Strong PM3_Supporting PP4

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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.1A>T	p.Met1?	initiator_codon_variant	2/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1A>T	p.Met1?	initiator_codon_variant	2/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2022	This sequence change affects the initiator methionine of the GAA mRNA. The next in-frame methionine is located at codon 122. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with Pompe disease (PMID: 18425781, 22252923, 29124014, 29422078, 31086307). ClinVar contains an entry for this variant (Variation ID: 984798). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GAA function (PMID: 22644586, 31301153). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 17, 2024	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) -

Computational scores

Source: dbNSFP v4.3

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;.;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.90	D;D;.;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	-0.26	T
PROVEAN	Benign	-0.19	.;.;N;N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.035	.;.;B;B
Vest4		0.67
MutPred		1.0		Loss of catalytic residue at M1 (P = 0.2704);Loss of catalytic residue at M1 (P = 0.2704);Loss of catalytic residue at M1 (P = 0.2704);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204467; hg19: chr17-78078386;