Submissions for variant NM_000152.5(GAA):c.1820G>A (p.Gly607Asp)

gnomAD frequency: 0.00001  dbSNP: rs1393386120

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001199946	SCV005089700	likely pathogenic	Glycogen storage disease, type II	2024-04-02	reviewed by expert panel	curation	The NM_000152.5:c.1820G>A variant in GAA is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 607 (p.Gly607Asp). Four probands with symptoms consistent with infantile-onset-Pompe disease have been reported with this variant (PMID: 29889338, 33301762, 37087815), three with documented deficiency of GAA activity (PMID: 33301762, 37097815) (PP4_Moderate). All of these probands are homozygous this variant. This variant is absent in both gnomAD 2.1.1 and 4.0.0 (PM2_Supporting). Expression of the variant in COS-7 cells resulted 2% wild-type GAA activity in one study (PMID: 14695532) and <2% wild-type GAA activity in a separate study (PMID: 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.872 which is above the threshold predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. Two other missense variants, c.1819G>T (p.Gly607Cys) (ClinVar Variation ID: 2118057) and c.1819G>A (p.Gly607Ser) (ClinVar Variation ID: 456385), in the same codon have been reported in patients with Pompe disease. However, these variants have not been classified by the ClinGen Lysosomal Diseases VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 932221). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM3, PS3_Moderate, PP4_Moderate, PM2_Supporting, PP3). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 2, 2024)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199946	SCV001370744	likely pathogenic	Glycogen storage disease, type II	2020-05-29	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1820G>A (p.Gly607Asp) 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 was absent in 246130 control chromosomes. c.1820G>A has been reported in the literature in at least one individual affected with Glycogen Storage Disease, Type 2 (Pompe Disease) in homozygous state (Hermans_2004). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Hermans_2004). 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 likely pathogenic.
Revvity Omics, Revvity	RCV001780105	SCV002025198	likely pathogenic	not provided	2021-02-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001199946	SCV002060045	likely pathogenic	Glycogen storage disease, type II	2021-11-16	criteria provided, single submitter	clinical testing	NM_000152.3(GAA):c.1820G>A(G607D) is a missense variant classified as likely pathogenic in the context of Pompe disease. G607D has been observed in cases with relevant disease (PMID: 27008195, 14695532, 29889338). Functional assessments of this variant are available in the literature (PMID: 14695532, 19862843). G607D has not been observed in population frequency databases. In summary, NM_000152.3(GAA):c.1820G>A(G607D) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001199946	SCV002281937	pathogenic	Glycogen storage disease, type II	2023-08-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GAA function (PMID: 14695532). 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. ClinVar contains an entry for this variant (Variation ID: 932221). This missense change has been observed in individual(s) with Pompe disease (PMID: 14695532, 29889338; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 607 of the GAA protein (p.Gly607Asp).
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV001199946	SCV003932130	pathogenic	Glycogen storage disease, type II	2023-06-14	criteria provided, single submitter	clinical testing	The heterozygous variant c.1820G>A (p.Gly607Asp) has been identified as a compound heterozygous state with the variant c.1524C>T (p.Gln509*). Phenotypes observed in the proband were cardiomegaly, feeding difficulties, delayed milestones, hepatomegaly and severe LV hypertrophy with severe LV dysfunction. This variant has been previously reported by Hermans MM et al., 2004.
Baylor Genetics	RCV001199946	SCV004197868	likely pathogenic	Glycogen storage disease, type II	2023-02-23	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001199946	SCV005046816	pathogenic	Glycogen storage disease, type II	2024-05-31	criteria provided, single submitter	clinical testing	A homozygous variant in exon 13 of the GAA gene that results in the amino acid substitution of glycine for aspartic acid at codon 607 was detected. The observed variant c.1820G>A (p.Gly607Asp) has not been reported in the 1000 genomes and gnomAD database. The in silico predictions is damaging by SIFT, MutationTaster and DANN. In summary, the variant meets our criteria to be classified as pathogenic.
Natera, Inc.	RCV001199946	SCV002092065	likely pathogenic	Glycogen storage disease, type II	2021-04-06	no assertion criteria provided	clinical testing