ClinVar Miner

Submissions for variant NM_001082971.2(DDC):c.1357C>T (p.Arg453Cys)

gnomAD frequency: 0.00001  dbSNP: rs142110773
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Medical Genetics Lab, Policlinico S. Orsola.Malpighi RCV000677176 SCV000788355 likely pathogenic Deficiency of aromatic-L-amino-acid decarboxylase 2018-07-30 criteria provided, single submitter clinical testing This variant is extremely rare (only one allele in ExAC). The affected arginine is completely conserved across 98 vertebrates and the observed missense substitution was evaluated as deleterious by different prediction programs (Polyphen2, SIFT and MutationTaster). The variant was found in a homozygous state in three patients of one single family. Patients showed a phenotype that was compatible with AADC deficiency and abnormalities of neurotransmitters and their metabolites in one patient's CSF supported pathogenicity.
Invitae RCV000677176 SCV004295200 pathogenic Deficiency of aromatic-L-amino-acid decarboxylase 2023-05-20 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with clinical features of aromatic L-amino acid decarboxylase deficiency (PMID: 25597765). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs142110773, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 453 of the DDC protein (p.Arg453Cys). This variant is also known as c.1123C>T (p.Arg375Cys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DDC function (PMID: 31953134). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DDC protein function. ClinVar contains an entry for this variant (Variation ID: 559481).

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