ClinVar Genomic variation as it relates to human health

A Homozygote Missense variant c.365C>T in Exon 6 of the HGD gene that results in the amino acid substitution p.Ala122Val was identified. The observed variant has a maximum allele frequency of 0.00006/--% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. This variant has been reported as Pathogenic/Likely Pathogenic in the ClinVar database (Variant ID: 418295). This variant was reported among the patients for Alkaptonuria (Vilboux et al., 2009). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 122 of the HGD protein (p.Ala122Val). This variant is present in population databases (rs544956641, gnomAD 0.04%). This missense change has been observed in individual(s) with alkaptonuria (PMID: 12501223, 19862842, 23430897, 25804398). ClinVar contains an entry for this variant (Variation ID: 188865). 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 HGD protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

The missense c.365C>Tp.Ala122Val variant in HGD gene has been reported previously in both homozygous and compound heterozygous state in multiple individuals affected with alkaptonuria Nemethova M, et al., 2016; Zatkova A, et al., 2012; Vilboux T, et al., 2009. The p.Ala122Val founder variant is identified as a founder variant amongst families Nemethova M, et al., 2016. The p.Ala122Val variant has been reported with allele frequency of 0.006% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submissions. The amino acid change p.Ala122Val in HGD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 122 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

The variant was originally described in AKU patient in PMID:12501223. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00031).