ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2140del (p.His714fs) (rs786204549)

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Total submissions: 4
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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 RCV000169264 SCV001371739 pathogenic Glycogen storage disease, type II 2020-02-14 reviewed by expert panel curation This variant, c.2140delC (p.His714Thrfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and no gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant has been reported in two patients who also carry a second variant in GAA. One of these cases meets the ClinGen LSD VCEP's specifications for PP4 and is compound heterozygous for p.His714Thrfs and a missense variant, c.1561G>A (p.Glu521Lys); the phase is unknown (PMID 17723315). The in trans data from this patient will be used in the assessment of p.Glu521Lys and, therefore, was not included here in order to avoid circular logic. The second case is compound heterozygous for the variant and c.-32-13T>G (PMID 30564623) but the GAA activity was not reported and PP4 cannot be assessed. There is a ClinVar entry for this variant (Variation ID: 188904, 2 star review status) with 2 submtters 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, PP4.
Counsyl RCV000169264 SCV000220555 likely pathogenic Glycogen storage disease, type II 2014-07-25 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725052 SCV000333554 pathogenic not provided 2015-08-12 criteria provided, single submitter clinical testing
Invitae RCV000169264 SCV000626534 pathogenic Glycogen storage disease, type II 2017-07-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His714Thrfs*50) 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 reported in an individual affected with Pompe disease (PMID: 17723315). ClinVar contains an entry for this variant (Variation ID: 188904). Loss-of-function variants in GAA are known to be pathogenic (PMID: 2252923, 18425781). For these reasons, this variant has been classified as Pathogenic.

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