rs786204614

Variant names:

• chr17-80104929-C-T
• rs786204614
• NM_000152.5:c.343C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_Supporting PM3_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000152.5(GAA):c.343C>T (p.Gln115Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least three individuals have been reported to have Pompe disease and this variant (PMIDs 17041744, 17616415, 32528171). GAA activity is reduced in the patients for whom it was reported (13-35% normal) but PP4 was not applied because the activity does not meet the strict thresholds specified by the ClinGen LD VCEP. ONe of these individuals is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.1076-1G>C, phase unknown (PMID:17616415). Two additional reports describe a child who is compound heterozygous for the variant and p.Pro482Leu (PMID:17041744, 17616415). The allelic data will be used in the classification of p.Pro482Leu and is not included here to avoid circular logic (PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 188996). 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 LD VCEP (specifications Version 2.0): PVS1, PM2_Supporting, PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274228/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 0.0660
• Publications: 4 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 10 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.

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.343C>T	p.Gln115*	stop_gained	Exon 2 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.343C>T	p.Gln115*	stop_gained	Exon 3 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.343C>T	p.Gln115*	stop_gained	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.343C>T	p.Gln115*	stop_gained	Exon 2 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.343C>T	p.Gln115*	stop_gained	Exon 3 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.343C>T	p.Gln115*	stop_gained	Exon 2 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Glycogen storage disease, type II (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.13	N
PhyloP100		0.066
Vest4		0.64
GERP RS		1.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs786204614; hg19: chr17-78078728;