17-80107817-C-G

Variant names:

• chr17-80107817-C-G
• rs763216519
• NM_000152.5:c.876C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4 PVS1 PM2

This summary comes from the ClinGen Evidence Repository: This variant, c.876C>G (p.Tyr292Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product. Therefore, PVS1 can be applied. Functional studies, in which the variant was expressed in COS cells revealed no GAA activity in the cells or medium. However, a faint band representing GAA protein was detectable on Western blot (PMID 31510962). As the experiment was done in an in vitro expression system, it is unclear whether any gene product would be made in vivo. This variant was absent in gnomAD v2.1.1, meeting PM2. Two patients with infantile onset Pompe disease from Thailand have been reported (PMID 31510962). The residual GAA activity was provided for one of them, meeting PP4. This patient is compound heterozygous for the variant and c.1003G>A (p.Gly335Arg). The in trans data from this patient was used in the assessment of p.Gly335Arg and is not included here in order to avoid circular logic. The other patient is homozygous, and both parents were confirmed to be carriers, but the residual GAA activity is not available, and this data will not be included. Therefore, PM3 is currently not met. There is a ClinVar entry for this variant (Variation ID: 637958, 0 star review status) with one submitter (an author of this paper) 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, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401363871/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: -2.90
• Publications: 2 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 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.
• 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.876C>G	p.Tyr292*	stop_gained	Exon 5 of 20	NP_000143.2
	GAA	NM_001079803.3		c.876C>G	p.Tyr292*	stop_gained	Exon 6 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.876C>G	p.Tyr292*	stop_gained	Exon 5 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.876C>G	p.Tyr292*	stop_gained	Exon 5 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.876C>G	p.Tyr292*	stop_gained	Exon 6 of 21	ENSP00000374665.3
	GAA	ENST00000933406.1		c.876C>G	p.Tyr292*	stop_gained	Exon 5 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: 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	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.19	N
PhyloP100		-2.9
Vest4		0.78
GERP RS		-6.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs763216519; hg19: chr17-78081616;