Submissions for variant NM_001082971.2(DDC):c.1339C>T (p.Arg447Cys)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471921	SCV002767564	pathogenic	Deficiency of aromatic-L-amino-acid decarboxylase	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with aromatic L-amino acid decarboxylase deficiency (AADC deficiency) (MIM#608643) (PMID: 33808712, PMID: 31104889, PMID: 24865461, PMID: 17240182). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 10 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Another variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The p.Arg447His variant has been observed in two patients with AADC deficiency (MIM#608643) in the literature, once in a homozygous state, and functional studies have shown this variant has decreased enzyme activity (PMID: 27147232, PMID: 17240182). (SP) 0803 - This variant has limited previous evidence of pathogenicity in two unrelated individuals. Two unrelated patients with AADC deficiency (MIM#608643) have been reported in literature both in a compound heterozygous state (PMID: 32111562, PMID: 32409695). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1005 - Clinically accredited laboratory assay specific to gene product shows abnormal protein function. This individual's CSF neurotransmitter tests are in keeping with AADC deficiency (The Children’s Hospital at Westmead). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002471921	SCV004020746	likely pathogenic	Deficiency of aromatic-L-amino-acid decarboxylase	2023-06-29	criteria provided, single submitter	clinical testing	Variant summary: DDC c.1339C>T (p.Arg447Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251398 control chromosomes (gnomAD). c.1339C>T has been reported in the literature in compound heterozygous individuals affected with Deficiency Of Aromatic-L-Amino-Acid Decarboxylase (e.g. Hyland_2020, Wen_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. In the HGMD dataset, a different missense variant (CM077527, p.Arg447His) has been classified as disease causing, indicating Arg447 may be a clinically significant residue. The following publications have been ascertained in the context of this evaluation (PMID: 32111562, 32409695). One ClinVar submitter has assessed the variant since 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV002471921	SCV004529719	likely pathogenic	Deficiency of aromatic-L-amino-acid decarboxylase	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 447 of the DDC protein (p.Arg447Cys). This variant is present in population databases (rs775312348, gnomAD 0.006%). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 32409695). 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: 1805503). 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%. This variant disrupts the p.Arg447 amino acid residue in DDC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17240182, 24865461, 27147232). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.