chr17-80108541-GG-C

Variant names:

• chr17-80108541-GG-C
• rs786204646
• NM_000152.5:c.1128_1129delGGinsC

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP4 PM3 PVS1 PM2

This summary comes from the ClinGen Evidence Repository: This variant, c.1128_1129delGGinsC (p.Trp376Cysfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. Two individuals have been reported who meet the ClinGen LSD VCEP’s specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768). There is a ClinVar entry for this variant (Variation ID: 189041, 2 star review status) with 3 submitters classifying the variant and pathogenic and one as likely 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, PM3, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274311/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 frameshift, missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 9.37
• Publications: 1 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: Pathogenic. The variant received 13 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.1128_1129delGGinsC	p.Trp376CysfsTer16	frameshift missense	Exon 7 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1128_1129delGGinsC	p.Trp376CysfsTer16	frameshift missense	Exon 8 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1128_1129delGGinsC	p.Trp376CysfsTer16	frameshift missense	Exon 7 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.1128_1129delGGinsC	p.Trp376CysfsTer16	frameshift missense	Exon 7 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1128_1129delGGinsC	p.Trp376CysfsTer16	frameshift missense	Exon 8 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1128_1129delGGinsC	p.Trp376CysfsTer16	frameshift missense	Exon 7 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Glycogen storage disease, type II (6)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs786204646; hg19: chr17-78082340;