ClinVar Miner

Submissions for variant NM_001082971.2(DDC):c.140C>A (p.Pro47His)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV003337943 SCV004048393 likely pathogenic Deficiency of aromatic-L-amino-acid decarboxylase criteria provided, single submitter clinical testing The c.140C>A (p.Pro47His) variant in DDC gene has been reported in homozygous state in individuals affected with aromatic L-amino acid decarboxylase (AADC) deficiency (Pons et al., 2004). The p.Pro47His variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid Pro at position 47 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Pro47His in DDC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Invitae RCV003337943 SCV004295204 pathogenic Deficiency of aromatic-L-amino-acid decarboxylase 2023-07-11 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 47 of the DDC protein (p.Pro47His). This variant is present in population databases (rs780542462, gnomAD 0.006%). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 15079002, 33996177). 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 DDC protein function. Experimental studies have shown that this missense change affects DDC function (PMID: 24865461). For these reasons, this variant has been classified as Pathogenic.

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