ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.841C>T (p.Arg281Trp)

gnomAD frequency: 0.00033  dbSNP: rs142967546
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV000535428 SCV001371697 likely pathogenic Glycogen storage disease, type II 2024-04-08 reviewed by expert panel curation The NM_000152.5:c.841C>T variant in GAA is predicted to result in the substitution of arginine by tryptophan at amino acid 281 (p.Arg281Trp). This variant has been reported in four individuals with features consistent with Pompe disease and documented GAA activity (PMID: 36299500, clinical diagnostic laboratory - pseudodeficiency variants were ruled out) and another individual with features consistent with infantile onset Pompe disease on enzyme replacement therapy but GAA activity not provided (PMID: 31086307). In addition, the variant was reported in an infant identified on newborn screen (PMID: 33202836), as well as in five individuals reported to have later-onset disease (PMID: 22081099, 33073009) (PP4_Moderate). Four patients are reported to be compound heterozygous for the variant and a pathogenic variant in GAA, including c.172C>T (p.Gln58Ter) (PMID: 36299500, phase unknown) (ClinVar Variation ID: 188903; SCV001371756.1), c.2481+102_2646+31del (clinical diagnostic laboratory; phase unknown) (ClinVar Variation ID: 657307), c.2161delG (clinical diagnostic laboratory; confirmed in trans) (ClinVar Variation ID: 932900, SCV001371755.1), and c.-32-13T>G (PMID: 33202836; phase unknown) (ClinVar Variation ID: 4027) (PM3_Strong). The score for the in silico meta-predictor REVEL, 0.786, suggests that the variant is deleterious, meeting PP3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (European non-Finnish), meeting PM2_Supporting. To our knowledge, the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 283894). This variant meets the criteria to the classified as likely pathogenic for Pompe disease. The classification was first approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2019. Since then, the data for this variant have been re-evaluated - no new data were identified. The classification of likely pathogenic was reapproved on April 8, 2024. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM3_Strong, PP4_Moderate, PP3, PM2_Supporting.
Eurofins Ntd Llc (ga) RCV000319725 SCV000336261 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000535428 SCV000626643 pathogenic Glycogen storage disease, type II 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 281 of the GAA protein (p.Arg281Trp). This variant is present in population databases (rs142967546, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Pompe disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 283894). 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%. This variant disrupts the p.Arg281 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000535428 SCV000796744 uncertain significance Glycogen storage disease, type II 2017-12-28 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV000319725 SCV002501636 likely pathogenic not provided 2022-02-23 criteria provided, single submitter clinical testing
GeneDx RCV000319725 SCV002574680 uncertain significance not provided 2022-06-13 criteria provided, single submitter clinical testing Identified in an individual with late-onset Pompe disease with significant residual GAA activity in muscle; a second variant in the GAA gene was not identified in this individual (Angelini et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 283894; ClinVar); This variant is associated with the following publications: (PMID: 33560568, 33202836, 34356580, 19343043, 22081099, 31086307, 23430949, 33717985, 33073009, 33073027)
Fulgent Genetics, Fulgent Genetics RCV000535428 SCV002777922 likely pathogenic Glycogen storage disease, type II 2021-10-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000535428 SCV003799213 likely pathogenic Glycogen storage disease, type II 2022-10-21 criteria provided, single submitter clinical testing The GAA c.841C>T; p.Arg281Trp variant (rs142967546) is reported in a carrier of Pompe disease identified by newborn screening (Wittmann 2012) and in an individual with suspected late onset Pompe disease who carried a second GAA variant (Ficicioglu 2020). The p.Arg281Trp variant is classified as likely pathogenic by an expert panel in ClinVar (Variation ID: 283894). It is found in the general population with an overall allele frequency of 0.02% (57/277866 alleles) in the Genome Aggregation Database. The arginine at codon 281 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.786). Based on available information, this variant is considered to be likely pathogenic. References: Ficicioglu C et al. Newborn Screening for Pompe Disease: Pennsylvania Experience. Int J Neonatal Screen. 2020 Nov 13;6(4):89. PMID: 33202836. Wittmann J et al. Newborn screening for lysosomal storage disorders in hungary. JIMD Rep. 2012;6:117-25. PMID: 23430949.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000535428 SCV003800660 likely pathogenic Glycogen storage disease, type II 2024-04-11 criteria provided, single submitter clinical testing Variant summary: GAA c.841C>T (p.Arg281Trp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain (IPR025887) of 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 0.00021 in 247128 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00021 vs 0.0042), allowing no conclusion about variant significance. c.841C>T has been reported in the literature in individuals affected with Glycogen Storage Disease (examples: Angelini_2012, Liao_2017, Kishnani_2019, Ficicioglu_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 283894). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity RCV000319725 SCV003828593 likely pathogenic not provided 2023-04-19 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000319725 SCV004010575 likely pathogenic not provided 2023-04-01 criteria provided, single submitter clinical testing GAA: PM3:Strong, PM2
Baylor Genetics RCV000535428 SCV004195434 likely pathogenic Glycogen storage disease, type II 2024-03-20 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000319725 SCV004227669 pathogenic not provided 2023-06-16 criteria provided, single submitter clinical testing PP3, PP4_moderate, PM2, PM3_very_strong
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000535428 SCV004847297 likely pathogenic Glycogen storage disease, type II 2023-07-07 criteria provided, single submitter clinical testing The p.Arg281Trp variant in GAA has been reported in at least 4 compound heterozygous individuals with biochemically confirmed Pompe disease and one compound heterozygous individual with sudden death under the age of 45 (Angelini 2011 PMID: 22081099, Kishnani 2019 PMID: 31086307, Salfati 2019 PMID: 31847883, Ficicoglu 2020 PMID: 33202836, ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel personal communication 2023). It has also been identified in 0.062% (42/67436) of European (non-Finnish) chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as likely pathogenic on December 5, 2019 by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (Variation ID 283894). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Pompe disease. ACMG/AMP Criteria applied: PM3_Strong, PP3, PP4.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000319725 SCV000925082 uncertain significance not provided 2011-02-17 no assertion criteria provided provider interpretation
Natera, Inc. RCV000535428 SCV001453416 uncertain significance Glycogen storage disease, type II 2019-12-13 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004751427 SCV005351834 likely pathogenic GAA-related disorder 2024-09-09 no assertion criteria provided clinical testing The GAA c.841C>T variant is predicted to result in the amino acid substitution p.Arg281Trp. This variant has been reported along with a second causative variant in individuals with late-onset Pompe disease (LOPD) or by newborn screening (Ficicioglu et al. 2020. PubMed ID: 33202836; Wencel et al. 2021. PubMed ID: 36299500). This variant was also reported in an individual with LOPD and an individual identified by newborn screening; a second variant was not identified in either individual (Angelini et al. 2012. PubMed ID: 22081099; Wittmann et al. 2012. PubMed ID: 23430949). It was also identified along with a likely benign intronic variant in an individual diagnosed with Pompe disease (Table S3, Kishnani et al. 2019. PubMed ID: 31086307). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from pathogenic to uncertain significance (http://www.ncbi.nlm.nih.gov/clinvar/variation/283894). The ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel interprets this variant as likely pathogenic and cites internal data from clinical diagnostic laboratories in their interpretation, mentioning the c.841C>T (p.Arg281Trp) variant was found with a second pathogenic variant (c.2481+102_2646+31del or c.2161del) in two individuals, with the variants confirmed to be on opposite alleles (i.e., in trans) in one of the individuals. Based on the collective evidence, we interpret this variant as likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.