ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.655G>A (p.Gly219Arg) (rs370950728)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen RCV000169462 SCV001371705 pathogenic Glycogen storage disease, type II 2020-04-19 reviewed by expert panel curation This variant, c.655G>A (p.Gly219Arg), has been reported in at least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP's specifications for PP4. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, including c.-32-13T>G (PMID 21550241, 24844452), c.169C>T (p.Gln57Ter) (PMID 29124014), or c.2560C>T (p.Arg854Ter)(PMID 23266370), and one is homozygous for the variant (PMID 25139343). This in trans data meets PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004024 in the African population, meeting PM2. When it was expressed in COS cells, this variant results in <2% wild type GAA activity and it is abnormally processed (PMIDs 14695532; 19862843), meeting PS3. The score for the REVEL in silico meta-predictor, 0.872, also supports that the variant has a deleterious impact on GAA function, meeting PP3. There is a ClinVar entry for this variant (Variation ID 189065; 2 star review status) with four submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP3, PP4.
Counsyl RCV000169462 SCV000220892 likely pathogenic Glycogen storage disease, type II 2014-11-19 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000481943 SCV000330942 pathogenic not provided 2015-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000481943 SCV000565024 pathogenic not provided 2017-02-28 criteria provided, single submitter clinical testing The G219R pathogenic variant in the GAA gene was first reported in an individual with infantile GSDII, who harbored an additional GAA variant (Fernandez-Hojas et al., 2002). G219R has subsequently been reported, in both the homozygous state and along with an additional GAA variant, in multiple individuals with GSDII (Hermans et al., 2004; Prater et al., 2013; Sacconi et al., 2014). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G219R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and missense variants in nearby residues (P217L; R224W/Q/P) have been reported in the Human Gene Mutation Database in association with GSDII (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000169462 SCV000626621 pathogenic Glycogen storage disease, type II 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 219 of the GAA protein (p.Gly219Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs370950728, ExAC 0.01%). This variant has been observed in several individuals affected with Pompe disease, including individuals with low alpha-glucosidase enzyme activity (less than 40% of normal), findings that are highly specific for this disease (PMID: 11738358, 14695532, 18429042, 21550241, 23266370, 23787031, 29124014, 23601496). ClinVar contains an entry for this variant (Variation ID: 189065). This variant has been reported to affect GAA protein function (PMID: 14695532). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169462 SCV000695664 pathogenic Glycogen storage disease, type II 2017-05-07 criteria provided, single submitter clinical testing Variant summary: The GAA c.655G>A (p.Gly219Arg) variant located in the Galactose mutarotase, N-terminal barrel domain (via InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120140 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). Multiple publications have cited the variant in both compound heterozygous and homozygous Pompe disease patients, which were found to have very little GAA activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000169462 SCV001422654 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Gly219Arg variant in GAA has been reported in 22 individuals (including 10 French, 3 Saudi, 1 Italian, 1 Spanish, 1 Japanese, and 3 other Caucasian individuals) with Glycogen Storage Disease II (PMID: 23787031, 30023291, 18995995, 23266370, 11738358, 21550241, 25037089, 23601496, 21637107, 29124014, 30155607, 18429042, 24844452, 14695532), and has also been reported pathogenic (by EGL, GeneDx, Invitae, and Integrated Genetics) and likely pathogenic (by Counsyl) in ClinVar (Variation ID: 189065). This variant has been identified in 0.004% (1/24848) of African chromosomes and 0.003% (1/35388) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs370950728). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Gly219Arg variant may reduce GAA activity by more than 98% (PMID: 14695532, 19862843). However, these types of assays may not accurately represent biological function. 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 combination with pathogenic and likely pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly219Arg variant is pathogenic (PMID: 21637107, 21550241, 11738358). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with very low GAA activity detected in relevant tissues (PMID: 23601496, 24844452, 21550241, 29124014, 11738358, 21637107). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies with COS cells transfected with this variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015).

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