ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1411_1414del (p.Glu471fs) (rs770276275)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169228 SCV000220494 likely pathogenic Glycogen storage disease, type II 2014-07-09 criteria provided, single submitter literature only
Invitae RCV000169228 SCV001209354 pathogenic Glycogen storage disease, type II 2019-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu471Profs*5) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs770276275, ExAC 0.02%). This variant has been observed in several individuals affected with infantile-onset Pompe disease (PMID: 8604985, 29046207, 18458862, 28394184). ClinVar contains an entry for this variant (Variation ID: 188874). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169228 SCV001362547 pathogenic Glycogen storage disease, type II 2019-10-24 criteria provided, single submitter clinical testing Variant summary: GAA c.1411_1414delGAGA (p.Glu471ProfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 249358 control chromosomes (gnomAD). c.1411_1414delGAGA has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). The variant has predominantly associated with infantile onset of the disease (e.g. Chien_2006, Labrousse_2010, Shieh_1996, Wan_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000169228 SCV001423056 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Glu471ProfsTer5 variant in GAA has been reported in 13 individuals from China or Taiwan with Glycogen Storage Disease II (PMID: 28394184, 18458862, 19948615, 10338092, 8604985), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 188874). This variant has been identified in 0.025% (5/19900) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770276275). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 471 and leads to a premature termination codon 5 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. The presence of this variant in combination with reported pathogenic and likely pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu471ProfsTer5 variant is pathogenic (PMID: 18458862, 19948615, 28394184; Variation ID: 189006, 4029). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected by assays with patient fibroblasts and/or lymphocytes (PMID: 18458862, 19948615, 28394184). 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 multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015).

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