rs786204507

Positions:

• chr17-80108383-TG-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: This variant, c.1051delG (p.Val351Cysfs), is a frameshift variant which is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The variant is absent in gnomAD v 2.1.1, meeting PM2. This variant has been reported in three individuals with Pompe disease and residual GAA activating meeting PP4 specifications (PMIDs 20033296, 20817528, 22676651). Two of these individuals are compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMIDs 20817528, 22676651). The other individual is compound heterozygous for the variant and c.1655T>C (p.Leu552Pro) (PMID 20033296). However, this in trans data will be used in the classification of p.Leu552Pro and is not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 24923245, 25455803). PM3_Supporting is met. There is a ClinVar entry for this variant (Variation ID 188841; 2 star review status) with one submitter classifying the variant as likely pathogenic and one a likely pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274024/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA ENST00000302262.8 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 1.50

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.1051del	p.Val351CysfsTer41	frameshift_variant	6/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1051del	p.Val351CysfsTer41	frameshift_variant	6/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461176 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 726898

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:7

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Val351CysfsTer41 variant in GAA has been reported in at least 8 individuals (including 1 German and 1 Northern European individual) with Glycogen Storage Disease II (PMID: 18425781, 22676651, 24923245, 25455803, 20817528), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL in ClinVar (Variation ID: 188841). This variant was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Val351CysfsTer41 variant may impact GAA levels and activity (PMID: 18425781). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 351 and leads to a premature termination codon 41 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. This variant has been seen in combination with a reported pathogenic variant in patients with Glycogen Storage Disease II (PMID: 22676651, 24923245, 25455803, 20817528). The phenotype of 3 individuals homozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in their leukocytes or fibroblasts (PMID: 20817528, 24923245). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and low GAA activity in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM2, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 19, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 13, 2023	This variant is present in population databases (rs786204507, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 188841). This premature translational stop signal has been observed in individuals with glycogen storage disease (PMID: 18425781, 29181627). This sequence change creates a premature translational stop signal (p.Val351Cysfs*41) 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, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 03, 2020	This variant, c.1051delG (p.Val351Cysfs), is a frameshift variant which is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The variant is absent in gnomAD v 2.1.1, meeting PM2. This variant has been reported in three individuals with Pompe disease and residual GAA activating meeting PP4 specifications (PMIDs 20033296, 20817528, 22676651). Two of these individuals are compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMIDs 20817528, 22676651). The other individual is compound heterozygous for the variant and c.1655T>C (p.Leu552Pro) (PMID 20033296). However, this in trans data will be used in the classification of p.Leu552Pro and is not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 24923245, 25455803). PM3_Supporting is met. There is a ClinVar entry for this variant (Variation ID 188841; 2 star review status) with one submitter classifying the variant as likely pathogenic and one a likely pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 29, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2023	Frameshift variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17027861, 18425781, 22252923, 20817528, 31392188, 22676651, 34852371, 30922962, 25455803, 29181627, 24923245, 20033296) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		Position offset: 26

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204507; hg19: chr17-78082182;