17-80117014-TG-TGG

Position:

chr17-80117014-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PVS1PP4

This summary comes from the ClinGen Evidence Repository: This variant, c.2242dup (p.Glu748Glyfs), is a frameshift variant predicted to cause a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD is 0.00001767 in the European, non-Finnish, population, meeting PM2. This variant has been reported in at least 2 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP’s PP4 specifications (PMIDs 9535769, 21484825). Both of these individuals are compound heterozygous for the variant and a unique variant, phase unknown; either c.1933G>A (p.Asp645Asn) (PMID 9535769) or c.1195-8G>A (PMID 21484825). In both cases, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID 370651; 2 star review status) with three submitters classifying the variant and 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 applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815662/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

GAA
NM_000152.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 9.45

Variant links:

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]

GAA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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.

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 linkuse as main transcript	c.2242dup	p.Glu748GlyfsTer48	frameshift_variant	16/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2242dup	p.Glu748GlyfsTer48	frameshift_variant	16/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250780

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1461388

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000567

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 15, 2016	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Glu748GlyfsTer48 variant in GAA has been reported in at least 5 individuals (including 2 from the UK, and 1 Italian individuals) with Glycogen Storage Disease II (PMID: 16917947, 9535769, 10206684, 21484825), and has also been reported likely pathogenic by Counsyl and pathogenic by GeneDx and EGL in ClinVar (Variation ID: 370651). This variant has been identified in 0.0018% (2/113202) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516659). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 748 and leads to a premature termination codon 48 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. The presence of this variant in combination with at least 2 pathogenic variants curated by our study and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu748GlyfsTer48 variant is pathogenic (PMID: 9535769, 29122469). The phenotype of two individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in fibroblasts (PMID: 9535769, 21484825). 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 multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 27, 2021	Variant summary: GAA c.2242dupG (p.Glu748GlyfsX48) 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 our laboratory (c.2501_2502delCA p.Thr834ArgfsX49; c.2544delC p.Lys849ArgfsX38). The variant allele was found at a frequency of 8e-06 in 250780 control chromosomes. c.2242dupG has been reported in the literature in multiple individuals affected with both infantile (example: Beesley_1998, Huie_1998) and late/adult (example: Montalvo_2006, Stepien_2016) onset forms of Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function: fibroblasts cultured from a patient with the variant of interest alongside a null variant showed <0.1% normal enzymatic activity (Huie_1998). Eight ClinVar submitters, including one expert panel (ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel) have assessed the variant since 2014: seven have classified the variant as pathogenic and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change creates a premature translational stop signal (p.Glu748Glyfs*48) 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 present in population databases (rs777275355, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with glycogen storage disease type II (PMID: 9535769, 16917947, 21484825, 29122469). This variant is also known as insGnt2243 and insG2242. ClinVar contains an entry for this variant (Variation ID: 370651). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 04, 2020	This variant, c.2242dup (p.Glu748Glyfs), is a frameshift variant predicted to cause a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD is 0.00001767 in the European, non-Finnish, population, meeting PM2. This variant has been reported in at least 2 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's PP4 specifications (PMIDs 9535769, 21484825). Both of these individuals are compound heterozygous for the variant and a unique variant, phase unknown; either c.1933G>A (p.Asp645Asn) (PMID 9535769) or c.1195-8G>A (PMID 21484825). In both cases, the in trans data from these patients will be used in the assessment of the second variant and was not included here in order to avoid a circular argument. There is a ClinVar entry for this variant (Variation ID 370651; 2 star review status) with three submitters classifying the variant and 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 applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2024	Reported in multiple patients with GSDII in published literature, including at least one patient who had biochemical testing that was diagnostic and consistent with the results seen in other patients with pathogenic variants in this gene (PMID: 10206684, 16917947, 21484825); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 17915575, 29122469, 26873529, 31254424, 34501319, 10206684, 16917947, 22644586, 9535769, 36046397, 21484825) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over