ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.444C>G (p.Tyr148Ter)

dbSNP: rs886043112
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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 RCV001789731 SCV002032140 pathogenic Glycogen storage disease, type II 2021-12-02 reviewed by expert panel curation The NM_000152.5:c.444C>G (p.Tyr148Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). One patient, with late onset Pompe disease, has been reported who responded to enzyme replacement therapy and had muscle histology consistent with Pompe disease (PMID 25093132)(PP4). This patient is compound heterozygous, phase unknown, for the variant and c.2238G>C (p.Trp746Cys). The allelic data for this patient will be used in the assessment of p.Trp746Cys and is not included here to avoid circular logic. The c.444C>G (p.Tyr148Ter) variant is absent in gnomAD v2.1.1 (PM2_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 (Specification Version 2.0): PVS1, PP4, PM2_Supporting (Approved by the ClinGen LSD VCEP - Oct. 19th, 2021)
Labcorp Genetics (formerly Invitae), Labcorp RCV001789731 SCV003442561 pathogenic Glycogen storage disease, type II 2022-04-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr148*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 25093132). ClinVar contains an entry for this variant (Variation ID: 1327503). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

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