ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The p.Glu762Lys variant in GAA has been reported in one individual with Glycogen Storage Disease II (PMID: 21488291). This variant has also been reported as a VUS by Invitae and Counsyl in ClinVar (Variation ID: 456399). This variant has been identified in 0.003% (1/30780) of South Asian chromosomes and 0.003% (3/111366) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs760063214). 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 762 is not highly conserved in mammals and evolutionary distant species, and 15 species (elephant, saker falcon, peregrine falcon, collared flycatcher, white-throated sparrow, medium ground finch, zebra finch, Tibetan ground jay, budgerigar, scarlet macaw, mallard duck, chicken, turkey, American alligator, and green sea turtle) carry a Lysine (Lys), raising the possibility that this change at this position may be tolerated. In summary, the clinical significance of the p.Glu762Lys 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 762 of the GAA protein (p.Glu762Lys). This variant is present in population databases (rs760063214, gnomAD 0.003%). This missense change has been observed in individual(s) with unspecified clinical presentation who showed low levels of acid alpha-glucosidase activity (PMID: 21488291). ClinVar contains an entry for this variant (Variation ID: 456399). 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 not 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.