ClinVar Genomic variation as it relates to human health

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).

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 460 of the GAA protein (p.Glu460Lys). This variant is present in population databases (rs771213237, gnomAD 0.003%). This missense change has been observed in individual(s) with a positive newborn screening result for GAA-related disease (PMID: 33202836). ClinVar contains an entry for this variant (Variation ID: 430460). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. 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.

Described as a variant of uncertain significance and identified in a patient with a positive newborn screen and decreased GAA activity who also harbored a pathogenic variant, however it is not known whether the variants occurred on the same (in cis) or opposite (in trans) chromosomes (PMID: 36246652); Identified in a patient with a positive newborn screen and decreased GAA activity who also harbored a likely pathogenic variant, however it is not known whether the variants occurred on the same (in cis) or opposite (in trans) chromosomes (PMID: 33202836); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19343043, 22253258, 37087815, 36246652, 33202836)