rs1057517286

Positions:

• chr17-80108605-CT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1193del (p.Leu398ArgfsTer42) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1. (PM2_Supporting). This variant has been reported in one patient with POmpe disease; however residual GAA activity was not provided and the second variant is not reported (PMID 30155607). There is a ClinVar entry for this variant (Variation ID: 371457). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16041891/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift, splice_region
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 1.02

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 Likely_pathogenic. Variant got 9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.1193del	p.Leu398ArgfsTer42	frameshift_variant, splice_region_variant	7/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.1193del	p.Leu398ArgfsTer42	frameshift_variant, splice_region_variant	7/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460492 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 726570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 26, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371457). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 30155607). This sequence change creates a premature translational stop signal (p.Leu398Argfs*42) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Mar 10, 2023	The NM_000152.5:c.1193del (p.Leu398ArgfsTer42) variant in GAA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1. (PM2_Supporting). This variant has been reported in one patient with POmpe disease; however residual GAA activity was not provided and the second variant is not reported (PMID 30155607). There is a ClinVar entry for this variant (Variation ID: 371457). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 09, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 30, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2022	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1057517286; hg19: chr17-78082404;