ClinVar Genomic variation as it relates to human health

Variant summary: DDC c.1040G>A (p.Arg347Gln) results in a conservative amino acid change located in the Pyridoxal phosphate-dependent transferase, major domain (IPR015421) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249548 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DDC causing Deficiency Of Aromatic-L-Amino-Acid Decarboxylase (4.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.1040G>A has been reported in the literature in multiple individuals affected with Deficiency Of Aromatic-L-Amino-Acid Decarboxylase (example Veerbeek_2007, Kuster_2018, Dai_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal decarboxylase activity towards L-Dopa substrate as observed by decreased steady state enzyme kinetic parameters (example, Montoli_2018). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

The c.1040G>A;p.(Arg347Gln) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 202181; PMID: 26994895; 24865461; 30144970; 30952622) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 24865461) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Pyridoxal_deC) - PM1. The variant is present at low allele frequencies population databases (rs201951824– gnomAD 0.0002629%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (PMID: 26994895) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 30144970) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.

ACMG classification criteria: PS3, PS4, PM2, PM3

Also observed with a second DDC variant in patients with AADC deficiency in published literature (Verbeek et al., 2007; Barth et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate severely reduced catalytic activity (Montioli et al., 2014; Montioli et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32369189, 17240182, 23430870, 20832343, 24865461, 26994895, 29356298, 30144970, 28100251, 31104889, 31975548, 27147232, 33763332, 32111562, 34426522, 34582790, 33083013)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 347 of the DDC protein (p.Arg347Gln). This variant is present in population databases (rs201951824, gnomAD 0.01%). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 17240182, 23430870, 30144970). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 202181). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.