rs200483245

Positions:

• chr17-80117047-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP4

This summary comes from the ClinGen Evidence Repository: This variant, c.2269C>T (p.Gln757Ter), which results in a premature termination codon, is expected to undergo nonsense medicated decay resulting in absence of gene product, meeting PVS1. The variant is absent in gnomAD v2.1.1, meeting PM2. One patient meeting the ClinGen LSD VCEP’s specifications for PP4 and compound heterozygous for this variant and c.925G>A (p.Gly309Arg) in GAA has been reported (PMID 24337590). The phase of the variants was not confirmed. In trans data from this patient was used in the assessment of p.Gly309Arg and was not included here in order to avoid circular logic. Additional cases have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 17723315, 29149851). There is a ClinVar entry for this variant (Variation ID: 429727, 2 star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for GSD 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/CA294856548/MONDO:0009290/010

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 3.74

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 (HGNC:):

ACMG classification

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	c.2269C>T	p.Gln757*	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	c.2269C>T	p.Gln757*	stop_gained	16/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461274 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726942

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

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	May 05, 2020	This variant, c.2269C>T (p.Gln757Ter), which results in a premature termination codon, is expected to undergo nonsense medicated decay resulting in absence of gene product, meeting PVS1. The variant is absent in gnomAD v2.1.1, meeting PM2. One patient meeting the ClinGen LSD VCEP's specifications for PP4 and compound heterozygous for this variant and c.925G>A (p.Gly309Arg) in GAA has been reported (PMID 24337590). The phase of the variants was not confirmed. In trans data from this patient was used in the assessment of p.Gly309Arg and was not included here in order to avoid circular logic. Additional cases have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 17723315, 29149851). There is a ClinVar entry for this variant (Variation ID: 429727, 2 star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for GSD Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gln757Ter variant in GAA has been reported in 1 Serbian, 1 Croatian, and 1 Canadian individuals with Glycogen Storage Disease II (PMID: 29149851, 24337590, 17723315), and has also been reported pathogenic by GeneDx and Counsyl in ClinVar (Variation ID: 429727). This variant was absent from genomes and no high quality genotypes at this site were noted to include this variant in exomes from the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200483245). This nonsense variant leads to a premature termination codon at position 757, 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 pathogenic variant in an individual with Glycogen Storage Disease II increases the likelihood that the p.Gln757Ter variant is pathogenic (PMID: 24337590). The phenotype of this individual compound heterozygous for this variant is highly specific for Glycogen Storage Disease II with less than 3% of normal GAA activity detected in their lymphocytes (PMID: 24337590). 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 the occurrence with a pathogenic GAA variant in an individual with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_supporting, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change creates a premature translational stop signal (p.Gln757*) 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: 17723315, 29149851). ClinVar contains an entry for this variant (Variation ID: 429727). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 02, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2015	The Q757X nonsense pathogenic variant in the GAA gene has been reported previously in a patient with adult-onsetGSDII, who also harbored the common c.-32-13 T>G variant (McCready et al., 2007). This pathogenic variant ispredicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNAdecay. The Q757X pathogenic variant was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.82	D
Vest4		0.95
GERP RS		1.9
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

Other links and lift over

dbSNP: rs200483245; hg19: chr17-78090846;