rs1207988953

Positions:

• chr17-80104963-GGT-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP4_Moderate PVS1 PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: NM_000152.5:c.379_380del (p.Cys127LeufsTer18) variant in GAA is a frameshift 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 4 patients with Pompe disease and this variant have been reported that meet the ClinGen LSD VCEP’s specifications for PP4_Moderate. Of these patients, the available data includes documentation of laboratory values showing GAA deficiency (PMIDs 18757064, 24245577, 24715333, 30049495, 33162552). Furthermore, one of these patients had documented features consistent with infantile onset Pompe disease (PMID 24715333, 33162552) and another was on enzyme replacement therapy (PMID 30049495)(PP4_Moderate). These patients are all compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.525delT (PMID 24715333, 33162552), “del exon 18” (PMID 9660056), and c.-32-13T>G (PMID 17573812, 17643989, 18757064, 24245577, 33458579; at least two patients). Total 2 points (PM3_Strong). Another patients is compound heterozygous for the variant and c.2104C>T (p.Arg702Cys); phase unconfirmed (PMID 30049495). The in trans data from this patient will be used in the assessment of p.Arg702Cys and was not included here in order to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 552747, two star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP Specification Version 2.0): PVS1, PM3_Strong, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658795227/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.57

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 15 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.379_380del	p.Cys127LeufsTer18	frameshift_variant	2/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.379_380del	p.Cys127LeufsTer18	frameshift_variant	2/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460220 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 726416

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:5

Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Aug 19, 2021	NM_000152.5:c.379_380del (p.Cys127LeufsTer18) variant in GAA is a frameshift 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 4 patients with Pompe disease and this variant have been reported that meet the ClinGen LSD VCEP’s specifications for PP4_Moderate. Of these patients, the available data includes documentation of laboratory values showing GAA deficiency (PMIDs 18757064, 24245577, 24715333, 30049495, 33162552). Furthermore, one of these patients had documented features consistent with infantile onset Pompe disease (PMID 24715333, 33162552) and another was on enzyme replacement therapy (PMID 30049495)(PP4_Moderate). These patients are all compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.525delT (PMID 24715333, 33162552), “del exon 18” (PMID 9660056), and c.-32-13T>G (PMID 17573812, 17643989, 18757064, 24245577, 33458579; at least two patients). Total 2 points (PM3_Strong). Another patients is compound heterozygous for the variant and c.2104C>T (p.Arg702Cys); phase unconfirmed (PMID 30049495). The in trans data from this patient will be used in the assessment of p.Arg702Cys and was not included here in order to avoid circular logic. The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 552747, two star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP Specification Version 2.0): PVS1, PM3_Strong, PP4_Moderate, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552747). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 9660056). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys127Leufs*18) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 19, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 strong -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1207988953; hg19: chr17-78078762;