ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1843G>A (p.Gly615Arg)

gnomAD frequency: 0.00001  dbSNP: rs549029029
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV000169115 SCV002583372 likely pathogenic Glycogen storage disease, type II 2022-09-06 reviewed by expert panel curation The NM_000152.5: c.1843G>A variant in GAA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 615 (p.Gly615Arg). At least 7 patients with a diagnosis of Pompe disease have been reported with this variant. Five of these patients are reported to have infantile onset Pompe disease (IOPD) and meet the criteria for PP4_Moderate with <10% GAA activity in cultured fibroblasts and/or GAA activity in the affected range in leukocytes (PMIDs: 15366815, 16860134, 18458862, 25037089), documented symptoms consistent with IOPD, and on enzyme replacement therapy (PMIDs: 16860134, 25037089) (PP4_Moderate). Of the reported patients, three are compound heterozygous, phase unknown, for another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, either c.2238G>A (p.Trp746Ter) (PMID: 16860134) or c.1935C>A (p.Asp645Glu) (PMID: 18458862) (2 patients). Two patients are homozygous for the variant (PMID: 15366815, 25037089) (PM3_Strong). A further two patients are compound heterozygous for the variant and either c.1832G>A (p.Gly611Asp) (PMID: 24269976) or c.1933G>C (p.Asp645His (clinical laboratory data) . The allelic data from these patients will be used in the classification of the other variant and is not included here to avoid circular. Finally, An 4 patients have been reported in the literature but the data was not included because the cDNA change for the variant was not provided, or does not match amino acid change (PMIDs: 10338092, 18607768, 21757382). The highest population minor allele frequency in gnomAD is 0.00022 in the East Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, the variant resulted in <2% GAA activity (PMID 19862843) (PS3_Supporting). The computational predictor REVEL gives a score of 0.989 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 188746, 2 star review status), with 5 submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Verions 2.0): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP3.
Counsyl RCV000169115 SCV000220317 likely pathogenic Glycogen storage disease, type II 2014-05-14 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV000169115 SCV000824487 pathogenic Glycogen storage disease, type II 2023-09-06 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: 19862843). 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: 188786). This missense change has been observed in individual(s) with Pompe disease (PMID: 10338092, 15366815, 16860134, 18458862, 18607768, 21757382, 24269976, 25037089). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs549029029, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 615 of the GAA protein (p.Gly615Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169115 SCV000919384 pathogenic Glycogen storage disease, type II 2018-07-05 criteria provided, single submitter clinical testing Variant summary: GAA c.1843G>A (p.Gly615Arg) 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 allele was found at a frequency of 2.1e-05 in 97298 control chromosomes (gnomAD and publication). The variant, c.1843G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), whom presented with significantly decreased enzyme activity (<10%). These data indicate that the variant is likely to be associated with disease. 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 pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000169115 SCV001422905 pathogenic Glycogen storage disease, type II 2020-01-22 criteria provided, single submitter curation The p.Gly615Arg variant in GAA has been reported in 13 individuals (including 4 Taiwanese, 1 Chinese, and 1 German individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 16860134, 18458862, 10338092, 24269976, 21232767, 20080426, 15366815, 18607768, 21757382, 25037089), and has also been reported likely pathogenic by Counsyl and pathogenic by Invitae and Integrated Genetics in ClinVar (Variation ID: 188786). This variant has been identified in 0.022% (4/17994) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs549029029). 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 provide some evidence that the p.Gly615Arg variant may impact protein function (PMID: 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 reported pathogenic variants in individuals with Glycogen Storage Disease II increases the likelihood that the p.Gly615Arg variant is pathogenic (PMID: 16860134, 18458862). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 21757382, 16860134, 18458862). 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, low frequency in the general population, and multiple occurrences in combination with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015).
Revvity Omics, Revvity RCV001781521 SCV002023813 pathogenic not provided 2023-02-27 criteria provided, single submitter clinical testing
GeneDx RCV001781521 SCV002756643 pathogenic not provided 2022-11-14 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18458862, 21757382, 24269976, 11738358, 31254424, 15366815, 18301443, 20080426, 12394636, 16860134, 19862843, 11949932, 29046207, 31953985, 30275481, 32711049, 32014045, 31086307, 21232767, 10338092, 18607768)
Fulgent Genetics, Fulgent Genetics RCV000169115 SCV002787554 pathogenic Glycogen storage disease, type II 2021-10-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV000169115 SCV004197792 pathogenic Glycogen storage disease, type II 2024-02-24 criteria provided, single submitter clinical testing
Natera, Inc. RCV000169115 SCV001459739 pathogenic Glycogen storage disease, type II 2020-09-16 no assertion criteria provided clinical testing

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