ClinVar Genomic variation as it relates to human health

Published protein folding and stability studies of the corresponding missense variant in yeast suggests this variant reduces the stability of yeast enolase (Zhao et al., 2018); however, the clinical significance of this finding in humans remains to be determined.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 18070103, 11506403)

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with beta-enolase deficiency. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (55 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated C-terminal TIM barrel domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an individual. The variant has previously been reported in a compound heterozygous patient with beta-enolase deficiency (ClinVar, OMIM, PMID: 11506403). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in a yeast model demonstrated that the variant results in a loss of function (PMID: 18070103). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 156 of the ENO3 protein (p.Gly156Asp). This variant is present in population databases (rs121918403, gnomAD 0.03%). This missense change has been observed in individual(s) with glycogen storage disease type XIII (PMID: 11506403). ClinVar contains an entry for this variant (Variation ID: 16617). 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 ENO3 protein function. Experimental studies have shown that this missense change affects ENO3 function (PMID: 18070103). 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.