Submissions for variant NM_000152.5(GAA):c.784G>A (p.Glu262Lys)

gnomAD frequency: 0.00004  dbSNP: rs201896815

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000169139	SCV002032128	pathogenic	Glycogen storage disease, type II	2021-08-25	reviewed by expert panel	curation	This variant, NM_000152.5(GAA):c.784G>A, is predicted to result in the substitution of glutamate to lysine at amino acid 262 (p.Glu262Lys). This variant represented 6.8% of alleles in an Italian case series of 29 infants with Pompe disease (PMID: 18429042). This variant has been reported in at least 20 individuals with Pompe disease, including at least 12 individuals with documented laboratory data showing deficiency of GAA activity and/or clinical symptoms consistent with infantile onset Pompe disease (cardiomegaly and muscle weakness), and/or on treated with enzyme replacement therapy (ERT) meeting the ClinGen LSD VCEP’s specifications for PP4_Moderate (PMID 11738358, 18285536, 19588081, 19948615, 25455803, 26497565, 27344650, 29181627, 29422078, 30023291, 31193175 31915562, 33228748)(PP4_Moderate). The variant has been reported in compound heterozygosity with a pathogenic variant in at least 8 patients, phase unconfirmed (PMID: 11738358, 18285536, 19948615, 24269976, 25455803, 29181627, 29422078, 29880332), and in at least 5 homozygous patients diagnosed with Pompe disease (PMIDs: 18429042, 26497565, 29422078, 33228748, 33325062) (PM3_Very Strong). More data is available in the literature but the maximum evidence for PM3_Very Strong has been reached. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, allowing this criterion to be applied (PM2_Supporting). The computational predictor REVEL gives a score of 0.888 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional studies have not been reported for this variant. There is a ClinVar entry for this variant (ClinVar variation ID: 188806) with 3 submitters classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specification Version 2.0): PM3_Very Strong, PP4_Moderate, PP3, PM2_Supporting. (Classification approved: August 17, 2021)
Counsyl	RCV000169139	SCV000220358	likely pathogenic	Glycogen storage disease, type II	2014-05-30	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169139	SCV000626642	pathogenic	Glycogen storage disease, type II	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 262 of the GAA protein (p.Glu262Lys). This variant is present in population databases (rs201896815, gnomAD 0.005%). This missense change has been observed in individual(s) with glycogen storage disease type II (Pompe disease) (PMID: 11738358, 18429042, 19588081, 21232767, 22658377, 27344650, 29422078, 31915562). 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: 188806). 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. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000727645	SCV000854936	pathogenic	not provided	2017-11-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169139	SCV000917388	pathogenic	Glycogen storage disease, type II	2018-02-19	criteria provided, single submitter	clinical testing	Variant summary: GAA c.784G>A (p.Glu262Lys) 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 1.4e-05 in 276972 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (1.4e-05 vs 0.0042), allowing no conclusion about variant significance. The c.784G>A variant has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169139	SCV001422941	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Glu262Lys variant in GAA has been reported in 14 individuals (including 6 Italian, 1 Brazilian, and 1 Chinese individuals) with Glycogen Storage Disease II (PMID: 22658377, 22980766, 26497565, 24269976, 24158270, 22958975, 22704482, 21232767, 19588081, 18429042), and has also been reported likely pathogenic by Counsyl and Invitae and pathogenic by EGL Genetic Diagnostics and Integrated Genetics in ClinVar (Variation ID: 188806). This variant has been identified in 0.005% (1/19938) of East Asian chromosomes and 0.002% (3/128794) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201896815). 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 presence of this variant in the homozygous state and in combination with 1 reported pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu262Lys variant is pathogenic (PMID: 26497565, 24158270). Individuals with this variant in the heterozygous and homozygous state have a highly specific phenotype for disease based on GAA enzyme activity assays (PMID: 26497565, 24158270). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PM2, PP3, PP4 (Richards 2015).
GeneDx	RCV000727645	SCV001817422	pathogenic	not provided	2021-01-18	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 31589614, 31915562, 26497565, 27344650, 29422078, 29181627, 25455803, 20080426, 24269976, 22980766, 27183828, 25466677, 19588081, 18429042, 22704482, 22958975, 26830551, 22658377, 21232767, 24158270, 11738358)
Revvity Omics, Revvity	RCV000727645	SCV002023839	pathogenic	not provided	2022-06-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169139	SCV002810948	likely pathogenic	Glycogen storage disease, type II	2021-11-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169139	SCV004195481	pathogenic	Glycogen storage disease, type II	2023-12-07	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000169139	SCV005051773	pathogenic	Glycogen storage disease, type II	2024-02-01	criteria provided, single submitter	curation
Natera, Inc.	RCV000169139	SCV002091962	pathogenic	Glycogen storage disease, type II	2021-06-08	no assertion criteria provided	clinical testing