Submissions for variant NM_000152.5(GAA):c.2269C>T (p.Gln757Ter)

dbSNP: rs200483245

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000664955	SCV001371730	pathogenic	Glycogen storage disease, type II	2020-05-05	reviewed by expert panel	curation	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.
GeneDx	RCV000493446	SCV000582366	pathogenic	not provided	2015-09-03	criteria provided, single submitter	clinical testing	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
Counsyl	RCV000664955	SCV000788999	pathogenic	Glycogen storage disease, type II	2017-01-03	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000664955	SCV001422609	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	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).
Invitae	RCV000664955	SCV001589424	pathogenic	Glycogen storage disease, type II	2024-01-14	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000493446	SCV002023816	pathogenic	not provided	2020-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000493446	SCV002563443	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000664955	SCV004197915	pathogenic	Glycogen storage disease, type II	2022-03-16	criteria provided, single submitter	clinical testing