ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.752C>T (p.Ser251Leu) (rs200856561)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000372885 SCV000407270 likely pathogenic Glycogen storage disease, type II 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000497864 SCV000590491 pathogenic not provided 2017-06-16 criteria provided, single submitter clinical testing The S251L and S254L missense variants in the GAA gene typically occur on the same chromosome (in cis) and are considered to be a common pathogenic variant (Labrousse et al., 2010). They have been reported in the homozygous state in individuals with Pompe disease as well as in individuals with Pompe disease with another GAA variant identified (Chien et al., 2011; Liao et al., 2014). Functional studies suggest that S251L and S254L result in decreased enzyme activity (Kroos et al., 2012).
Invitae RCV000372885 SCV000626637 likely benign Glycogen storage disease, type II 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000372885 SCV001132198 likely pathogenic Glycogen storage disease, type II 2019-06-11 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000372885 SCV001423076 likely pathogenic Glycogen storage disease, type II 2020-01-29 no assertion criteria provided curation The [p.Ser251Leu; p.Ser254Leu] complex variant in GAA has been reported in at least 15 individuals with Glycogen Storage Disease II (PMID: 24513544, 21232767, 27183828, 20080426), and has also been reported likely pathogenic by Illumina, pathogenic by GeneDx, and likely benign by Invitae in ClinVar (Variation ID: 325781, 325782). This variant has been identified in <0.28% of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200856561). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. In vitro functional studies provide some evidence that the p.Ser251Leu variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in the homozygous state and with a reported pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Ser251Leu variant is pathogenic (PMID: 24513544, 21232767). The phenotype of homozygotes and heterozygotes with this variant is highly specific for Glycogen Storage Disease II based on GAA activity assays in relevant tissues and the absence of known pseudodeficiency alleles, consistent with disease (PMID: 24513544, 21232767). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PP4_moderate, PM3 (Richards 2015).

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