Submissions for variant NM_000152.5(GAA):c.842G>A (p.Arg281Gln)

gnomAD frequency: 0.00001  dbSNP: rs772607616

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001071217	SCV005359929	uncertain significance	Glycogen storage disease, type II	2024-08-06	reviewed by expert panel	curation	The NM_000152.5:c.842G>A variant in GAA is a missense variant predicted to cause substitution of Arg by Gln at amino acid 281 (p.Arg281Gln). To our knowledge, this variant has not been reported in the literature in a patient with Pompe disease and the results of functional studies are not available. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00028 (2/7098 alleles) in the Other population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2 (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.747 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. Another missense variant (c.841C>T, p.Arg281Trp) (PMID: 23430949, ClinVar Variation ID 283894) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 864108). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_supporting, PP3, PM5_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on August 6, 2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071217	SCV001236508	likely pathogenic	Glycogen storage disease, type II	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 281 of the GAA protein (p.Arg281Gln). This variant is present in population databases (rs772607616, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 864108). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001568545	SCV001792434	uncertain significance	not provided	2021-01-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Genome-Nilou Lab	RCV001071217	SCV002027239	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001568545	SCV003834075	uncertain significance	not provided	2022-04-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155354	SCV003845154	uncertain significance	not specified	2023-02-24	criteria provided, single submitter	clinical testing	Variant summary: GAA c.842G>A (p.Arg281Gln) results in a conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 246712 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.842G>A in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. A different variant located at the same amino acid has been classified as likely pathogenic by our lab and an expert panel (p.Arg281Trp). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One submitter classified as likely pathogenic while three classified as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001071217	SCV001453417	uncertain significance	Glycogen storage disease, type II	2020-02-13	no assertion criteria provided	clinical testing