ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1655T>C (p.Leu552Pro) (rs779556619)

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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 RCV000381512 SCV001371750 pathogenic Glycogen storage disease, type II 2020-04-20 reviewed by expert panel curation This variant, c.1655T>C (p.Leu552Pro), has been reported in at least 14 patients with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP's specifications for PP4 (PMIDs 12213618, 12923862, 16838077, 18285536, 19046416, 20033296, 25681614, 27666774). Of these patients, three are compound heterozygous for the variant and a pathogenic variant in GAA, phase unknown - either (c.377G>A (p.Trp126Ter) (PMID 25681614), c.989G>A (p.Trp330Ter) (PMID 12923862) or c.1051delG (PMID 20033296) - and two are homozygous for the variant (PMIDs 19046416, 27666774). This in trans data meets PM3_Strong. Additional patients meeting PP4 have been reported but the in trans data will be used in the classification of the other variant and therefore was not included here, including c.1856G>A (p.Ser619Asn) (PMID 16838077), c.854C>G (p.Pro285Arg) (PMID 12213618), and c.-32-3C>A (PMID 19046416). Further patients with this variant have been reported to have Pompe disease but the data was not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 14695532, 16917947, 18429042, 18607768, 19588081, 25052852, 25998610, 27927596, 28490439, 29122469, 29422078, 29653542, 30155607), or the cDNA sequence for the variant was not provided (PMID 17616415). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 in the European non-Finnish population, meeting PM2. This variant has been shown to result in significantly decreased GAA activity (<5%) and abnormal processing when expressed in COS cells (PMIDs 12213618, 14695532, 19862843), meeting PS3. The score for the REVEL meta-predictor, 0.94, also supports that the variant has a deleterious impact on GAA function, meeting PP3. There is a ClinVar entry for this variant (Variation ID: 279811, 2 star review status) with six submitters all classifying the variant as pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specific by the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP3, PP4.
GeneDx RCV000288533 SCV000329355 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing The L552P variant in the GAA gene has been reported previously in multiple unrelated individuals with Pompe disease (Bodamer et al. 2002; Palermo et al. 2012; Remiche et al. 2014). Expression studies in COS-7 cells found that L552P is associated with approximately 2.5% residual acid alpha-glucosidase activity compared to wild type (Flanagan et al. 2009). The L552P variant is observed in 7/111590 (0.0063%) alleles from individuals of non-Finnish European background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). L552P is a semi-conservative amino acid substitution located within the catalytic domain of the protein at a position that is conserved across species (Flanagan et al. 2009). We interpret L552P as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000288533 SCV000331328 pathogenic not provided 2018-04-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000381512 SCV000695645 pathogenic Glycogen storage disease, type II 2016-09-02 criteria provided, single submitter clinical testing Variant summary: The GAA c.1655T>C (p.Leu552Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120282 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). The variant has been identified in many Pompe patients in the literature in homozygous and compound heterozygous state. In at least one patient with a compound heterozygous genotype, leukocyte GAA enzyme residual activity was 18.78% of normal, indicating that this variant has significantly reduced activity. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000381512 SCV000894162 pathogenic Glycogen storage disease, type II 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000381512 SCV000962864 pathogenic Glycogen storage disease, type II 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 552 of the GAA protein (p.Leu552Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs779556619, ExAC 0.002%). This variant has been observed to be homozygous or in combination with another GAA variant in many individuals affected with Pompe disease (PMID: 24158270, 27666774, 18607768, 14695532, 17616415, 25681614, 20638881, 19588081). ClinVar contains an entry for this variant (Variation ID: 279811). Experimental studies have shown that this missense change severely decreases GAA activity and processing (PMID: 19862843, 25036864, 14695532, 25409744, 17213836). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000288533 SCV001245690 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Counsyl RCV000381512 SCV000485575 pathogenic Glycogen storage disease, type II 2016-07-19 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000381512 SCV001422884 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Leu552Pro variant in GAA has been reported in 26 individuals (including 5 Italian, 5 Brazilian, 4 German, 2 Spanish, and 2 Greek individuals) with Glycogen Storage Disease II, segregated with disease in 6 affected relatives from 3 families (PMID: 12923862, 19862843, 12213618, 22658377, 16838077, 18285536, 25681614, 16917947, 14695532, 17616415, 18607768, 19588081, 24158270, 23160972), and has also been reported pathogenic (by GeneDx, EGL, Counsyl, and Integrated Genetics/Laboratory Corporation of America) in ClinVar (Variation ID: 279811). This variant has been identified in 0.007% (8/111590) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs779556619). 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.Leu552Pro variant may impact GAA processing, levels, and activity (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 reported pathogenic or likely pathogenic variants in individuals with Glycogen Storage Disease II increases the likelihood that the p.Leu552Pro variant is pathogenic (PMID: 12923862, 12213618, 16838077, 18285536, 25681614, 16917947, 24158270; Variation ID: 371622, 550327, 550355). The phenotype of an individual homozygous or compound heterozygous for this variant is highly specific for Glycogen Storage Disease II with <10% GAA activity detected in their muscle, lymphocyte, and muscle cells (PMID: 16917947, 12213618, 20033296, 12923862, 27666774, 19046416, 16838077, 24158270, 25681614, 18285536). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on multiple occurrences with likely pathogenic and pathogenic variants in Glycogen Storage Disease II and in vitro functional studies with COS cells transfected with this variant. ACMG/AMP Criteria applied: PM3, PS3, PM2, PP3, PP4 (Richards 2015).

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