rs761317813

Variant names:

• chr17-80104837-TC-T
• rs761317813
• NM_000152.5:c.258delC

Your query was ambiguous. Multiple possible variants found:

• chr17-80104837-TC-T
• chr17-80104837-TC-TCC

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.258del (p.Asn87ThrfsTer55) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2 of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID:551592). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. 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 ). The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 7, 2021. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 5, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA502402192/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: -0.512

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.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.258delC	p.Asn87ThrfsTer55	frameshift_variant	Exon 2 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.258delC	p.Asn87ThrfsTer55	frameshift_variant	Exon 2 of 20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459918 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726322

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:3

Oct 10, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000152.5:c.258del (p.Asn87ThrfsTer55) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2 of 20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in patients with Pompe disease. There is a ClinVar entry for this variant (Variation ID:551592). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. 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 ). The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 7, 2021. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 5, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs761317813; hg19: chr17-78078636;