17-80108600-TC-TCC

Position:

• chr17-80108600-TC-TCC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM3_Supporting PM2 PVS1 PP4

This summary comes from the ClinGen Evidence Repository: This variant, c.1192dup (p.Leu398ProfsTer108), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This variant is not in gnomAD v2.1.1, meeting PM2. One patient has been reported who meets the ClinGen LSD VCEP’s specifications for PP4 and who is compound heterozygous with c.-32-13T>G pathogenic variant, phase unknown (PMID 17616415), meeting PM3_Supporting. The variant has been reported in additional publications but GAA activity was not provided and therefore the data was not included (PMIDs 22980766, 27711114). There is a ClinVar entry for this variant (Variation ID: 370510, 1 star review status) with one submitter classifying the variant 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, PM2, PM3_supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041890/MONDO:0009290/010

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 frameshift, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 0.427

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 12 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.1192dupC	p.Leu398fs	frameshift_variant, splice_region_variant	7/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1192dupC	p.Leu398fs	frameshift_variant, splice_region_variant	7/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

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, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 20, 2020	This variant, c.1192dup (p.Leu398ProfsTer108), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This variant is not in gnomAD v2.1.1, meeting PM2. One patient has been reported who meets the ClinGen LSD VCEP's specifications for PP4 and who is compound heterozygous with c.-32-13T>G pathogenic variant, phase unknown (PMID 17616415), meeting PM3_Supporting. The variant has been reported in additional publications but GAA activity was not provided and therefore the data was not included (PMIDs 22980766, 27711114). There is a ClinVar entry for this variant (Variation ID: 370510, 1 star review status) with one submitter classifying the variant 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, PM2, PM3_supporting, PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 23, 2016	- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057516546; hg19: chr17-78082399;