Submissions for variant NM_001082971.2(DDC):c.478C>T (p.Arg160Trp)

dbSNP: rs886062374

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000279143	SCV000469601	uncertain significance	Deficiency of aromatic-L-amino-acid decarboxylase	2017-04-28	criteria provided, single submitter	clinical testing	The DDC c.478C>T (p.Arg160Trp) variant is a missense variant that has been identified in a compound heterozygote state with a second missense variant in one individual with aromatic L-amino acid decarboxylase deficiency (Barth et al. 2011). The AADC enzymatic activity in the patient was 8% of the mean of the child reference range, confirming AADC enzyme deficiency. Control data are unavailable for the p.Arg160Trp variant, and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium despite being located in a region of good sequencing coverage. The variant is thus presumed to be rare. The evidence for this variant is limited. The p.Arg160Trp variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for aromatic L-amino acid decarboxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000279143	SCV002259654	pathogenic	Deficiency of aromatic-L-amino-acid decarboxylase	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 160 of the DDC protein (p.Arg160Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 23430870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 360437). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DDC function (PMID: 29356298). This variant disrupts the p.Arg160 amino acid residue in DDC. Other variant(s) that disrupt this residue have been observed in individuals with DDC-related conditions (PMID: 31975548), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.