ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1051del (p.Val351fs) (rs786204507)

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Total submissions: 5
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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 RCV000169190 SCV001371764 pathogenic Glycogen storage disease, type II 2020-05-03 reviewed by expert panel curation This variant, c.1051delG (p.Val351Cysfs), is a frameshift variant which is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The variant is absent in gnomAD v 2.1.1, meeting PM2. This variant has been reported in three individuals with Pompe disease and residual GAA activating meeting PP4 specifications (PMIDs 20033296, 20817528, 22676651). Two of these individuals are compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMIDs 20817528, 22676651). The other individual is compound heterozygous for the variant and c.1655T>C (p.Leu552Pro) (PMID 20033296). However, this in trans data will be used in the classification of p.Leu552Pro and is not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 24923245, 25455803). PM3_Supporting is met. There is a ClinVar entry for this variant (Variation ID 188841; 2 star review status) with one submitter classifying the variant as likely pathogenic and one a likely pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.
Counsyl RCV000169190 SCV000220435 likely pathogenic Glycogen storage disease, type II 2014-06-19 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725759 SCV000339223 pathogenic not provided 2016-02-16 criteria provided, single submitter clinical testing
Invitae RCV000169190 SCV001400792 pathogenic Glycogen storage disease, type II 2019-08-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val351Cysfs*41) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in multiple individuals affected with glycogen storage disease (PMID: 18425781, 29181627). ClinVar contains an entry for this variant (Variation ID: 186998). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000169190 SCV001422879 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Val351CysfsTer41 variant in GAA has been reported in at least 8 individuals (including 1 German and 1 Northern European individual) with Glycogen Storage Disease II (PMID: 18425781, 22676651, 24923245, 25455803, 20817528), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL in ClinVar (Variation ID: 188841). This variant was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. 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.Val351CysfsTer41 variant may impact GAA levels and activity (PMID: 18425781). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 351 and leads to a premature termination codon 41 amino acids downstream. This alteration is then 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. This variant has been seen in combination with a reported pathogenic variant in patients with Glycogen Storage Disease II (PMID: 22676651, 24923245, 25455803, 20817528). The phenotype of 3 individuals homozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in their leukocytes or fibroblasts (PMID: 20817528, 24923245). 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 low GAA activity in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM2, PP4 (Richards 2015).

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