Submissions for variant NM_000152.5(GAA):c.1958C>A (p.Thr653Asn)

gnomAD frequency: 0.00001  dbSNP: rs763456921

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001249044	SCV005619830	likely pathogenic	Glycogen storage disease, type II	2024-07-21	reviewed by expert panel	curation	The NM_000152.5:c.1958C>A variant in GAA is a missense variant predicted to cause substitution of threonine by asparagine at amino acid 653 (p.Thr653Asn). At least three probands with Pompe disease have been reported with this variant (PMIDs 21232767, 24513544, clinical laboratory data), two with documented deficiency of GAA activity (PMID: 23884227, 25612604) (PP4_Moderate). One patient is compound heterozygous for (c.1958C>A p.Thr653Asn) and (c.752 C>T; 761 C>T, p.Ser251Leu; Ser254Leu, P/LP haplotype based on classification by the ClinGen Lysosomal Diseases VCEP); phase confirmed by parental testing (1 point, PMID: 21232767). Another patient was identified on newborn screen, currently asymptomatic, therefore data not included, compound heterozygous for the variant and c.424_440del17 (PMID: 24513544). Another patient is compound heterozygous for the variant and c.1551G>T. The allelic data from this patient may be used in the classification of c.1551 and is not include here to avoid circular logic (PMID: 29995633). Total 1 point (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002548 (5/19624 alleles) in the East Asian population, which is lower than the ClinGen LD VCEP's threshold (<0.001) for meeting PM2_Supporting (PM2_Supporting). The computational predictor REVEL gives a score of 0.748 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 972798). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Expert panel on July 21, 2024).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249044	SCV001422986	uncertain significance	Glycogen storage disease, type II	2020-01-15	criteria provided, single submitter	curation	The p.Thr653Asn variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 29995633, 21232767, 24513544) and has been identified in 0.025% (5/19624) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs763456921). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts and lymphocytes being <1% of wild type, consistent with disease (PMID: 21232767, 24513544). This variant has been reported in combination with reported pathogenic and likely pathogenic variants and in individuals with glycogen storage disease II (VariationID: 555986; PMID: 21232767, 24513544, 29995633). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PP4 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001249044	SCV001573915	pathogenic	Glycogen storage disease, type II	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 653 of the GAA protein (p.Thr653Asn). This variant is present in population databases (rs763456921, gnomAD 0.02%). This missense change has been observed in individual(s) with Pompe disease (PMID: 21232767, 24513544). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 972798). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001249044	SCV004195473	likely pathogenic	Glycogen storage disease, type II	2024-02-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001249044	SCV005653229	likely pathogenic	Glycogen storage disease, type II	2024-03-26	criteria provided, single submitter	clinical testing