Submissions for variant NM_000152.5(GAA):c.1441T>C (p.Trp481Arg)

gnomAD frequency: 0.00002  dbSNP: rs772883420

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000169391	SCV004227917	pathogenic	Glycogen storage disease, type II	2023-10-01	reviewed by expert panel	curation	The NM_000152.5:c.1441T>C variant in GAA is predicted to result in the missense substitution of tryptophan by arginine at amino acid 481 (p.Trp481Arg). The variant has been reported in at least 6 individuals with Pompe disease in compound heterozygosity with another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. It was confirmed in trans with c.1326+1G>A (PMIDs: 10189220, 9862843), and was found in unconfirmed phase with c.-32-13T>G (PMID: 14695532, 18757064, 22676651, 27189384, 29556838, 34357340); c.2560C>T (p.Arg854Ter) (PMIDs: 31086307, 35787971), c.1979G>A (p.Arg660His) (PMID: 31086307), and c.2481+102_c.2646+31del (PMID: 26497565, 28657663). Another patient is compound heterozygous for the variant and c.1556T>C (p.Met519Thr) (PMID: 31086307); the allelic data from this patient will be used in the assessment of the other variant and is not included here to avoid circular logic (PM3_Strong). This variant has been reported in individuals with specific phenotypic features of Pompe disease including documented laboratory values revealing GAA deficiency, individuals on enzyme replacement therapy, patients with documented symptoms of infantile onset Pompe disease, and elevated urine Hex4 (PMID: 26497565, 28657663, 31086307, 34357340) (PP4_Moderate). Trp481 is a residue that crystallography studies have shown to be important in the architecture of the active site and substrate binding of GAA; this residues has, therefore, has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf, PMID: 29061980) (PM1). In two independent studies, expression of the variant in COS cells results in <2% GAA activity compared to normal, but also a significant amount of mature GAA protein, suggesting that the variant impacts catalysis rather than protein production or stability (PMID: 14695532, 19862843). The computational predictor REVEL gives a score of 0.967 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: ). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PM1, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting, (Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 1, 2023)
Counsyl	RCV000169391	SCV000220783	likely pathogenic	Glycogen storage disease, type II	2014-10-10	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169391	SCV000919383	pathogenic	Glycogen storage disease, type II	2018-06-22	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1441T>C (p.Trp481Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 276888 control chromosomes. c.1441T>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), with reported severely deficient GAA enzyme activity (Tsai_2017, Hermans_2004, Herzog_2012, Raben_1998, van Capelle2016). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169391	SCV000956690	pathogenic	Glycogen storage disease, type II	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 481 of the GAA protein (p.Trp481Arg). This variant is present in population databases (rs772883420, gnomAD 0.008%). This missense change has been observed in individual(s) with Pompe disease (PMID: 18757064; Invitae). 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: 189007). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532, 19862843). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169391	SCV001422626	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Trp481Arg variant in GAA has been reported in 6 individuals (including 1 African American and 1 German individuals) with Glycogen Storage Disease II (PMID: 27189384, 18757064, 10189220, 19862843, 26497565, 22676651, 14695532, 28657663), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae and Integrated Genetics in ClinVar (Variation ID: 189007). This variant has been identified in 0.008% (2/24904) of African chromosomes and 0.003% (4/128730) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs772883420). 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 provide some evidence that the p.Trp481Arg variant may impact ligand binding and GAA activity but not GAA levels (PMID: 19862843, 14695532, 15501829). However, these types of assays may not accurately represent biological function. 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 presence of this variant in combination with pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Trp481Arg variant is pathogenic (PMID: 26497565, 22676651, 27189384, 28657663). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on very low GAA activity in assays with relevant tissue (PMID: 26497565, 22676651, 27189384, 28657663). In summary, this variant meets criteria to be classified as pathogenic for p.Trp481Arg in an autosomal recessive manner based on in vitro functional evidence and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015).
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000169391	SCV001448809	likely pathogenic	Glycogen storage disease, type II	2017-02-09	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV002223801	SCV002502520	pathogenic	not provided	2021-10-12	criteria provided, single submitter	clinical testing
GeneDx	RCV002223801	SCV002599637	pathogenic	not provided	2022-10-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31254424, 19862843, 21228398, 28657663, 22676651, 18757064, 15501829, 16580018, 31086307, 10189220, 14695532, 26497565, 27189384, 33202836, 29556838, 27535533, 22253258, 19343043)
Revvity Omics, Revvity	RCV002223801	SCV003822618	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169391	SCV004197806	pathogenic	Glycogen storage disease, type II	2024-03-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169391	SCV001455617	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing