rs771317809

chr7-50470140-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001082971.2(DDC):c.1073G>A(p.Arg358His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R358C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DDC NM_001082971.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.30

Genes affected

DDC (HGNC:2719): (dopa decarboxylase) The encoded protein catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine. Defects in this gene are the cause of aromatic L-amino-acid decarboxylase deficiency (AADCD). AADCD deficiency is an inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency. Multiple alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 7-50470140-C-T is Pathogenic according to our data. Variant chr7-50470140-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 379626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DDC	NM_001082971.2	c.1073G>A	p.Arg358His	missense_variant	12/15	ENST00000444124.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DDC	ENST00000444124.7	c.1073G>A	p.Arg358His	missense_variant	12/15	1	NM_001082971.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251392 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461044 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726912

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000112 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of aromatic-L-amino-acid decarboxylase Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 17, 2016	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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.;T;.;.;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.7	D;.;.;.;D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;.;.;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D
Vest4		0.86
MutPred		0.95		Loss of MoRF binding (P = 0.0412);.;.;.;.;.;Loss of MoRF binding (P = 0.0412);
MVP		0.87
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs771317809; hg19: chr7-50537838; COSMIC: COSV105275111;