ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.784G>A (p.Glu262Lys) (rs201896815)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169139 SCV000220358 likely pathogenic Glycogen storage disease, type II 2014-05-30 criteria provided, single submitter literature only
Invitae RCV000169139 SCV000626642 pathogenic Glycogen storage disease, type II 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 262 of the GAA protein (p.Glu262Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs201896815, ExAC 0.01%). This variant has been observed in individual(s) with glycogen storage disease type II (Pompe disease) (PMID: 31915562, 11738358, 18429042, 19588081, 22658377, 21232767, 29422078, 27344650). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188806). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727645 SCV000854936 pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169139 SCV000917388 pathogenic Glycogen storage disease, type II 2018-02-19 criteria provided, single submitter clinical testing Variant summary: GAA c.784G>A (p.Glu262Lys) results in a conservative amino acid change located in the Glycoside hydrolase family 31, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 276972 control chromosomes. This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (1.4e-05 vs 0.0042), allowing no conclusion about variant significance. The c.784G>A variant has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000169139 SCV001422941 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Glu262Lys variant in GAA has been reported in 14 individuals (including 6 Italian, 1 Brazilian, and 1 Chinese individuals) with Glycogen Storage Disease II (PMID: 22658377, 22980766, 26497565, 24269976, 24158270, 22958975, 22704482, 21232767, 19588081, 18429042), and has also been reported likely pathogenic by Counsyl and Invitae and pathogenic by EGL Genetic Diagnostics and Integrated Genetics in ClinVar (Variation ID: 188806). This variant has been identified in 0.005% (1/19938) of East Asian chromosomes and 0.002% (3/128794) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201896815). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in combination with 1 reported pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Glu262Lys variant is pathogenic (PMID: 26497565, 24158270). Individuals with this variant in the heterozygous and homozygous state have a highly specific phenotype for disease based on GAA enzyme activity assays (PMID: 26497565, 24158270). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PM2, PP3, PP4 (Richards 2015).

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