Submissions for variant NM_001082971.2(DDC):c.1073G>A (p.Arg358His)

gnomAD frequency: 0.00001  dbSNP: rs771317809

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000445005	SCV000516849	pathogenic	not provided	2015-05-14	criteria provided, single submitter	clinical testing	The R358H variant in the DDC gene has been reported previously in association with AADC deficiency,in an affected individual who was compound heterozygous for the R358H variant and another loss offunction variant. This individual's plasma AADC activity was significantly reduced as compared tonormal AADC activity (Verbeek et al., 2007). The R358H substitution was not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The R358H variant is a conservativechange at a position that is conserved across species. In silico analysis predicts this variant is probablydamaging to the protein structure/function. A missense variant in a nearby residue (R347Q) has beenreported in the Human Gene Mutation Database in association with AADC deficiency (Stenson et al.,2014), supporting the functional importance of this region of the protein. We interpret R358H as a pathogenic variant.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000578157	SCV000680011	likely pathogenic	Deficiency of aromatic-L-amino-acid decarboxylase	2016-10-17	criteria provided, single submitter	clinical testing	The NM_001082971.1(DDC):c.1073G>A in exon 12 of the DDC gene is predicted to create a change of an arginine to an histidine at amino acid position 358, NP_001076440.1(DDC):p.p.(Arg358His), which is considered not significant. The arginine at this position has very highly conservation but however, Grantham assessment (A-GVGD) is unlikely pathogenic. In silico software predicts this variant to be disease causing. It is situated in a Pyridoxal phosphate-dependent decarboxylase conserved domain. This variant has not been previously observed in our cohort but is present in a population database at a frequency of 0.002%. It has been previously reported in compound heterozygous state in a patient with aromatic -L-amino decarboxylase deficiency (AADC) and functional studies showed reduced enzyme activity (Verbeek MM. et al.,2007). Based on current information, and in association with the NM_001082971.1(DDC):c.1352G>T variant, this variant has been classified as LIKELY PATHOGENIC. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with AADC.
Invitae	RCV000578157	SCV002176705	likely pathogenic	Deficiency of aromatic-L-amino-acid decarboxylase	2022-10-17	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects DDC function (PMID: 29356298). 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. 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. ClinVar contains an entry for this variant (Variation ID: 379626). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 358 of the DDC protein (p.Arg358His). This variant is present in population databases (rs771317809, gnomAD 0.003%). This missense change has been observed in individual(s) with DDC-related conditions (PMID: 17240182, 32369189).