ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.925G>A (p.Gly309Arg) (rs543300039)

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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 RCV000169127 SCV001371746 pathogenic Glycogen storage disease, type II 2020-04-20 reviewed by expert panel curation This variant, c.925G>A (p.Gly309Arg), has been reported in at least 5 patients with Pompe disease who meet the specifications for PP4 (PMIDs 16838077, 23430847, 23601496, 27189384, doi:10.21767/2380-7245.100010). One of these individuals is homozygous for the variant (PMID 23601496), and three individuals are compound heterozygous for the variant and a pathogenic variant in GAA; either c.-32-13T>G (PMID 16838077), c.2269C>T (p.Gln757Ter) (PMID 23430847), or c.2608C>T (p.Arg870Ter) (doi:10.21767/2380-7245.100010), meeting PM3_Strong. Additional patients have been reported but were not included because the residual GAA enzyme activity was not reported and therefore PP4 cannot be assessed (PMIDs 9660056, 16917947, 23402890, 24245577), a patient with the same genotype has already been included (PMID 24495340), or the cDNA sequence for the variant was not provided (PMID 17616415). When expressed in COS cells, this variant resulted in no increase in GAA activity and showed evidence of abnormal processing (PMIDs 9660056, 19862843), meeting PS3. The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00004544 in the European non-Finnish population, meeting PM2. The deleterious impact of this variant is also supported by the in silico meta-predictor, REVEL (score 0.963), meeting PP3. There is a ClinVar entry for this variant (Variation ID: 188797; 2 star review status) with 4 submitters all classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP3, PP4.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723463 SCV000700458 pathogenic not provided 2017-01-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169127 SCV000919381 pathogenic Glycogen storage disease, type II 2018-05-24 criteria provided, single submitter clinical testing Variant summary: GAA c.925G>A (p.Gly309Arg) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain 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 4.6e-05 in 108582 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (4.6e-05 vs 0.0042), allowing no conclusion about variant significance. c.925G>A 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. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169127 SCV000938984 pathogenic Glycogen storage disease, type II 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 309 of the GAA protein (p.Gly309Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs543300039, ExAC 0.02%). This variant has been observed as homozygous or in combination with another GAA variant in many individuals affected with Pompe disease (PMID: 9660056, 17616415, 29122469, 17210890, 23601496, 24495340, 16917947, 24245577). ClinVar contains an entry for this variant (Variation ID: 188797). Experimental studies have shown that this missense change leads to the production of non-functional alpha-glucosidase enzyme in vitro (PMID: 9660056). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000169127 SCV001365781 pathogenic Glycogen storage disease, type II 2019-04-24 criteria provided, single submitter clinical testing The p.Gly309Arg variant in GAA has been reported in the homozygous or compound heterozygous state in >10 individuals with Pompe disease (Kroos 1998, Kroos 2006, Montalvo 2006, Elder 2013, Hansel 2018). It has also been identified in 0.01% (1/9898) of Ashkenazi Jewish and 0.005% (5/110036) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported as Pathogenic and Likely Pathogenic in ClinVar (Variation ID 188797). Computational prediction tools and conservation analysis are consistent with pathogenicity. Additionally, an in vitro functional study supports an impact on protein function (Kroos 1998). In summary, the p.Gly309Arg variant meets criteria to be classified as pathogenic for autosomal recessive Pompe disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PP3, PS3_Supporting.
Counsyl RCV000169127 SCV000220337 pathogenic Glycogen storage disease, type II 2016-03-09 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000169127 SCV001422908 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Gly309Arg variant in GAA has been reported in at least 20 individuals (including 8 Dutch, 1 French, 1 Croatian, 1 Hispanic, 1 Greek) with Glycogen Storage Disease II, and segregated with disease in at least 4 affected relatives from 2 families (PMID: 9660056, 23430847, 27189384, 17616415, 23402890, 16917947, 24495340, 23601496, 16838077, 24245577; DOI: 10.21767/2380-7245.100010). This variant has also been reported likely pathogenic by Counsyl and pathogenic by EGL in ClinVar (Variation ID: 188797). This variant has been identified in 0.010% (1/9898) of Ashkenazi Jewish chromosomes, (5/110036) of 0.004% European (non-Finnish) chromosomes, and 0.003% (1/30458) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs543300039). 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 and pulse-chase analysis provide evidence that the p.Gly309Arg variant impacts GAA activity (PMID: 9660056). 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 a pathogenic variant and in homozygosity in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly309Arg variant is pathogenic (PMID: 24495340, 23601496, 16838077). The phenotype of an individual homozygous or compound heterozygous for this variant is highly specific for Glycogen Storage Disease II with low GAA activity in leukocytes (PMID: 23430847, 23601496, 24495340, 17616415, DOI: 10.21767/2380-7245.100010). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on occurrences with a reported pathogenic variant in individuals with Glycogen Storage Disease II and other findings from the literature. ACMG/AMP Criteria applied: PM3, PM2, PP3, PP4, PS3 (Richards 2015).

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