ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1378G>A (p.Glu460Lys) (rs771213237)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492864 SCV000583265 likely pathogenic not provided 2018-11-06 criteria provided, single submitter clinical testing The E460K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E460K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (Y455C/F; P457H/L; D459N; G461S; L462P) have been reported in the Human Gene Mutation Database in association with GSDII (Stenson et al., 2014), supporting the functional importance of this region of the protein. This substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000492864 SCV000708330 uncertain significance not provided 2017-05-04 criteria provided, single submitter clinical testing
Counsyl RCV000670619 SCV000795494 uncertain significance Glycogen storage disease, type II 2017-11-08 criteria provided, single submitter clinical testing
Invitae RCV000670619 SCV001562122 uncertain significance Glycogen storage disease, type II 2020-09-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 460 of the GAA protein (p.Glu460Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs771213237, ExAC 0.005%). This variant has not been reported in the literature in individuals with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 430460). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Institute Rare Disease Group, Broad Institute RCV000670619 SCV001422899 uncertain significance Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Glu460Lys variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS by EGL Genetic Diagnostics and Counsyl and a likely pathogenic variant by GeneDx in ClinVar (Variation ID: 430460). This variant has been identified in 0.003% (1/30602) of South Asian chromosomes and 0.003% (3/112884) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs771213237). 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 do not provide strong support for or against an impact to the protein. However, the Glutamate (Glu) at position 460 is highly conserved in mammals and evolutionary distant species, raising the possibility that a change at this position may not be tolerated. In summary, the clinical significance of the p.Glu460Lys variant is uncertain. ACMG/AMP Criteria applied: PM2 (Richards 2015).

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