ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2608C>T (p.Arg870Ter) (rs780321415)

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Total submissions: 9
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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 RCV000169394 SCV001371741 pathogenic Glycogen storage disease, type II 2020-02-14 reviewed by expert panel curation This variant, c.2608C>T (p.Arg870Ter), is a nonsense variant that is expected to result in nonsense mediated decay and absence of gene product. This is supported by the lack of cross reactive immunological material in cultured fibroblasts from a patient with this variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting the ClinGen LSD VCEP's threshold for PM2. This variant has been reported in patients meeting the ClinGen LSD VCEP's PP4 criterion who also carry a known pathogenic variant in GAA, either c.-32-13T>G or c.525delT, phase unknown (PMIDs 17723315, 26497565), and a patient who is homozygous for the variant (PMID 26497565). Therefore, PP4 and PM3 can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMID 28763149), or a case with the same variant (not confirmed in trans) had already been included (PMID 17056254, 22676651). There is a ClinVar entry for this variant (Variation ID: 189009, 2 star review status) with five 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. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4.
Counsyl RCV000169394 SCV000220788 likely pathogenic Glycogen storage disease, type II 2014-10-14 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723528 SCV000700543 pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000723528 SCV000890293 pathogenic not provided 2019-01-11 criteria provided, single submitter clinical testing The R870X variant has been reported in a patient with infantile onset glycogen storage disease II (GSDII) who was homozygous for the R870X variant (Swift et al., 2017). The R870X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R870X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret this variant as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000169394 SCV000893479 pathogenic Glycogen storage disease, type II 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000169394 SCV001223553 pathogenic Glycogen storage disease, type II 2020-01-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg870*) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs780321415, ExAC 0.002%). This variant has been observed in several individuals affected with Pompe disease (PMID: 17056254, 27344650, 29181627). ClinVar contains an entry for this variant (Variation ID: 189009). 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. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169394 SCV001339199 pathogenic Glycogen storage disease, type II 2020-03-05 criteria provided, single submitter clinical testing Variant summary: GAA c.2608C>T (p.Arg870X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.7e-05 in 225354 control chromosomes (gnomAD). c.2608C>T has been reported in the literature in multiple compound heterozygous- and homozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. McCready_2007, Palmer_2007, Swift_2016, Banugaria_2013, Loscher_2018). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Therapies Laboratory,Murdoch University RCV000169394 SCV001244230 pathogenic Glycogen storage disease, type II 2019-01-07 no assertion criteria provided research Adult form; onset in third decade; normal size and amount of mRNA for GAA, GAA protein detected by antibody, but only 9 to 26% of normal acid-alpha-1,4 glucosidase activity
Broad Institute Rare Disease Group,Broad Institute RCV000169394 SCV001422606 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Arg870Ter variant in GAA has been reported in 9 individuals (including 2 Brazilian, 2 from the UK, 1 Spanish, 1 German, and 1 Hispanic individuals) with Glycogen Storage Disease II (PMID: 23843830, 22676651, 17056254, 17723315, 26497565, 23825616, 19588081, 25681614), and has also been reported pathogenic by EGL and likely pathogenic by Counsyl in ClinVar (Variation ID: 189009). This variant has been identified in 0.005% (5/102290) of European (non-Finnish) chromosomes and 0.003% (1/31448) of Latino chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs780321415). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 870, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with 2 pathogenic variants and in homozygosity in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg870Ter variant is pathogenic (PMID: 22676651, 26497565). The phenotype of an individual homozygous or compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on their low GAA activity detected (PMID: 26497565, 22676651). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015).

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