rs1800312

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM3PM2PVS1PP4PS3

This summary comes from the ClinGen Evidence Repository: This variant, c.2238G>A (p.Trp746Ter), is a nonsense variant, predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. This is supported by the finding that patients with this variant have no GAA cross-reactive immunological material in protein isolated from cultured skin fibroblasts (i.e. CRIM-negative) (PMID 22252923), as well as functional studies in which there was no measurable GAA activity when the variant was expressed in HEK-293 cells (PMID 23430493). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in the African population, meeting PM2. This variant has been reported in 3 patients who meet the ClinGen LSD VCEP’s specifications for PP4. Two of these patients are compound heterozygous for pathogenic variants, either c.-32-13T>G or c.1826dupA (PMIDs 16860134, 22613277, 25741864). The phase is unknown. This data meets PM3. Another patient is compound heterozygous for the variant and c.1843G>A (p.Gly615Arg). This in trans data was used in the assessment of p.Gly615Arg and therefore was not included here in order to avoid circular logic. There is a ClinVar entry for this variant (ClinVar variation ID: 270904, 2 star review status) with 3 submitters classifying 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 applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815666/MONDO:0009290/010

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GAA
NM_000152.5 stop_gained

Scores

5

1

1

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PS3

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 linkuse as main transcript	c.2238G>A	p.Trp746Ter	stop_gained	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.2238G>A	p.Trp746Ter	stop_gained	16/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

4

AN:

152200

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

2

AN:

250832

Hom.:

0

AF XY:

0.00000737

AC XY:

1

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.0000617

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

3

AN:

1461374

Hom.:

0

Cov.:

31

AF XY:

0.00000275

AC XY:

2

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

4

AN:

152200

Hom.:

0

Cov.:

33

AF XY:

0.0000134

AC XY:

1

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

1

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	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Trp746Ter variant in GAA has been reported in at least 2 Caucasian and 1 Asian individuals with Glycogen Storage Disease II (PMID: 16860134, 22613277, 25741864), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL Genetic Diagnostics, GeneDx, and Invitae in ClinVar (Variation ID: 370904). This variant has been identified in 0.004% (1/24930) of African chromosomes and 0.002% (2/128684) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1800312). 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 HEK293 cells transfected with this variant provide some evidence that the p.Trp746Ter variant may impact GAA processing and activity (PMID: 23430493). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 746, which is 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 a reported pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Trp746Ter variant is pathogenic (PMID: 22613277). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in an assay of skin fibroblasts (PMID: 16860134, 22613277). One additional pathogenic variant, c.2237G>A (p.Trp746Ter), with the same position and amino acid change has been reported in association with disease (PMID: 26497565, 10206684, 12923862, 16917947, 18429042, 18285536, 21484825, 22980766, 24158270, 22237443, 24169249, 25488666, 25526786, 24269976, 17056254). 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 frequency in the general population. ACMG/AMP Criteria applied: PVS1, PM2, PM3_Supporting, PP4 (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 11, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 30, 2021	Variant summary: GAA c.2238G>A (p.Trp746X) 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. The variant allele was found at a frequency of 8e-06 in 250832 control chromosomes. c.2238G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Kishnani_2006, Patel_2012, Mori_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal GAA activity as measured following transient expression in HEK293 cells (Nino_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/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 12, 2023	This sequence change creates a premature translational stop signal (p.Trp746*) 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 (rs1800312, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with Pompe disease (PMID: 16860134, 22613277, 29122469). ClinVar contains an entry for this variant (Variation ID: 370904). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 19, 2022	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 05, 2020	This variant, c.2238G>A (p.Trp746Ter), is a nonsense variant, predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. This is supported by the finding that patients with this variant have no GAA cross-reactive immunological material in protein isolated from cultured skin fibroblasts (i.e. CRIM-negative) (PMID 22252923), as well as functional studies in which there was no measurable GAA activity when the variant was expressed in HEK-293 cells (PMID 23430493). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 in the African population, meeting PM2. This variant has been reported in 3 patients who meet the ClinGen LSD VCEP's specifications for PP4. Two of these patients are compound heterozygous for pathogenic variants, either c.-32-13T>G or c.1826dupA (PMIDs 16860134, 22613277, 25741864). The phase is unknown. This data meets PM3. Another patient is compound heterozygous for the variant and c.1843G>A (p.Gly615Arg). This in trans data was used in the assessment of p.Gly615Arg and therefore was not included here in order to avoid circular logic. There is a ClinVar entry for this variant (ClinVar variation ID: 270904, 2 star review status) with 3 submitters classifying 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 applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4 -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2021	Published functional studies demonstrate the variant results in reduced GAA activity (Nino et al., 2013); Not observed at a significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in 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: 26889246, 22613277, 25525159, 23457621, 22252923, 25741864, 26685070, 18519449, 29880332, 29122469, 10206684, 28726123, 33741225, 27655474, 26497565, 16860134, 23430493) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

D

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

46

DANN

Uncertain

1.0

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

D

MutationTaster

Benign

1.0

A;A

Vest4

0.97

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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

Other links and lift over

dbSNP: rs1800312; hg19: chr17-78090815;