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

gnomAD frequency: 0.00033  dbSNP: rs142967546

Total submissions: 16

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	2019-12-05	reviewed by expert panel	curation	This variant, c.841C>T (p.Arg281Trp), has been identified by a clinical diagnostic laboratory in three individuals who meets the ClinGen LSD VCEP's specifications for PP4_Moderate. All three individuals are compound heterozygous for the variant and a pathogenic variant in GAA; either c.2481+102_2646+31del (phase unknown), c.172C>T (p.Gln58Ter) (phase unknown), or c.2161delG (confirmed in trans). This data meets PM3_Strong. In addition, the variant was reported in a patient with late onset Pompe disease with no second variant identified (PMID 22081099), and a heterozygous individual identified on newborn screen (PMID 23430949). 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. To our knowledge, the results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 283894; 2 star review status) with 4 submitters all classifying the variant as a variant of uncertain significance. However, based on the unpublished clinical laboratory data available, this variant meets the criteria to the classified as likely pathogenic for Pompe disease. ACMG/AMP criteria met: PM2, PM3_Strong, PP3, PP4_Moderate.
Eurofins Ntd Llc (ga)	RCV000319725	SCV000336261	uncertain significance	not provided	2017-12-15	criteria provided, single submitter	clinical testing
Invitae	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	2023-01-18	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 (gnomAD). This frequency is not higher than predicted 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 may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters (including ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=4) and VUS (n=4). 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	2023-10-23	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