rs763216519

Positions:

• chr17-80107817-C-G
• chr17-80107817-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP4

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

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 Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.876C>G	p.Tyr292Ter	stop_gained	5/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.876C>G	p.Tyr292Ter	stop_gained	5/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing;in vitro	Department of Pediatrics, Division of Medical Genetics, Faculty of Medicine Ramathibodi Hospital, Mahidol University	Jul 10, 2019	The c.876C>G creates a premature protein product p.Y292* resulting from early termination of protein synthesis. This variant has not been reported in the literature in individuals with GAA-related disease. The c.876C>G (p.Y292*) located at N-terminal of beta-sheet domain, is predicted to eliminate most of the enzyme, including the catalytic domain. In vitro expression analysis of c.876C>G (p.Y292*) indicates that this mutation lead to undetectable GAA activity in both cell lysate and culture medium and prohibited secretion of the precursor form completely. We interpret this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Oct 05, 2020	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. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	A;A
Vest4		0.78
GERP RS		-6.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs763216519; hg19: chr17-78081616;