rs1428358278

Positions:

• chr17-80118711-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM3 PVS1 PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000152.5(GAA):c.2706del variant in GAA is a frameshift variant predicted to cause a premature stop codon (p.Lys903ArgfsTer2). Although the predicted termination codon occurs in the penultimate exon, it is more than 50 base pairs upstream from the 3' end of the exon, and therefore, predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is supported by the finding of a patient with this variant who has no GAA cross reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (PMID 22252923) (PVS1). Three patients have been reported with deficient GAA activity in either dried blood spots (in the affected range based on clinical laboratory data) or cultured fibroblasts (<1% normal activity) (personal communication, PMIDs 22252923, 31710733) (PP4_Moderate). One of these patients is compound heterozygous, phase unknown, for the variant and a pathogenic variant in GAA, c.-33-13T>G ( PMID:31710733), and another is homozygous for the variant (PMID:22252923, personal communication) (PM3). A patient is compound heterozygous for c.2706del and c.2051C>T (p.Pro684Leu). The alleic data from this patient will be used in the classification of p.Pro684Leu and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 554339, 2 star review status) with 2 submitters reporting the variant as 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 met, as specific by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658795297/MONDO:0009290/010

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GAA NM_000152.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 0.293

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.2706delG	p.Lys903fs	frameshift_variant	19/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.2706delG	p.Lys903fs	frameshift_variant	19/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

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	Sep 06, 2022	The NM_000152.5(GAA):c.2706del variant in GAA is a frameshift variant predicted to cause a premature stop codon (p.Lys903ArgfsTer2). Although the predicted termination codon occurs in the penultimate exon, it is more than 50 base pairs upstream from the 3' end of the exon, and therefore, predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is supported by the finding of a patient with this variant who has no GAA cross reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (PMID 22252923) (PVS1). Three patients have been reported with deficient GAA activity in either dried blood spots (in the affected range based on clinical laboratory data) or cultured fibroblasts (<1% normal activity) (personal communication, PMIDs 22252923, 31710733) (PP4_Moderate). One of these patients is compound heterozygous, phase unknown, for the variant and a pathogenic variant in GAA, c.-33-13T>G ( PMID: 31710733), and another is homozygous for the variant (PMID: 22252923, personal communication) (PM3). A patient is compound heterozygous for c.2706del and c.2051C>T (p.Pro684Leu). The alleic data from this patient will be used in the classification of p.Pro684Leu and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 554339, 2 star review status) with 2 submitters reporting the variant as 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 met, as specific by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PM3, PP4_Moderate, PM2_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 30, 2021	Variant summary: GAA c.2706delG (p.Lys903ArgfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by HGMD. The variant was absent in 250632 control chromosomes (gnomAD). c.2706delG has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example: Bali_2012, Khan_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic(n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change creates a premature translational stop signal (p.Lys903Argfs*2) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 22252923). ClinVar contains an entry for this variant (Variation ID: 554339). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2023	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -38

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

Publications

LitVar

Other links and lift over

dbSNP: rs1428358278; hg19: chr17-78092510;