ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1654del (p.Leu552fs)

dbSNP: rs2039246615
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV001200867 SCV001371754 pathogenic Glycogen storage disease, type II 2020-04-20 reviewed by expert panel curation This variant, c.1654del (p.Leu552SerfsTer26), is a frameshift variant which is predicted to result in a premature termination codon and nonsense mediated decay resulting in lack of gene product. This is supported by absence of cross-reactive immunological material on Western blot of protein from cultured skin fibroblasts from an individual with this variant (PMID 22252923). Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. One patient with infantile-onset Pompe disease and residual GAA activity meeting PP4 specifications has been reported. This patient is compound heterozygous for the variant and c.2560C>T (p.Arg854Ter) (PMIDs 25741864, 27493997, 29122469), meeting PM3_Supporting. There is no ClinVar entry for this variant. In summary, this 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001200867 SCV003442523 pathogenic Glycogen storage disease, type II 2022-06-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu552Serfs*26) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 932899). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 22252923, 31086307). This variant is not present in population databases (gnomAD no frequency).

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