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NM_001082971.2(DDC):c.1357C>T (p.Arg453Cys) AND Deficiency of aromatic-L-amino-acid decarboxylase

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
May 20, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000677176.2

Allele description [Variation Report for NM_001082971.2(DDC):c.1357C>T (p.Arg453Cys)]

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

Gene:
DDC:dopa decarboxylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p12.2
Genomic location:
Preferred name:
NM_001082971.2(DDC):c.1357C>T (p.Arg453Cys)
HGVS:
  • NC_000007.14:g.50463317G>A
  • NG_008742.1:g.107140C>T
  • NM_000790.4:c.1357C>T
  • NM_001082971.2:c.1357C>TMANE SELECT
  • NM_001242886.2:c.1243C>T
  • NM_001242887.2:c.1213C>T
  • NM_001242888.2:c.1123C>T
  • NM_001242889.2:c.1078C>T
  • NP_000781.2:p.Arg453Cys
  • NP_001076440.2:p.Arg453Cys
  • NP_001229815.2:p.Arg415Cys
  • NP_001229816.2:p.Arg405Cys
  • NP_001229817.2:p.Arg375Cys
  • NP_001229818.2:p.Arg360Cys
  • NC_000007.13:g.50531015G>A
  • NM_001242888.1:c.1123C>T
Protein change:
R360C
Links:
dbSNP: rs142110773
NCBI 1000 Genomes Browser:
rs142110773
Molecular consequence:
  • NM_000790.4:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001082971.2:c.1357C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242886.2:c.1243C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242887.2:c.1213C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242888.2:c.1123C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242889.2:c.1078C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Deficiency of aromatic-L-amino-acid decarboxylase
Synonyms:
DDC deficiency; Aromatic amino acid decarboxylase deficiency; Dopa decarboxylase deficiency
Identifiers:
MONDO: MONDO:0012084; MedGen: C1291564; Orphanet: 35708; OMIM: 608643

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000788355Medical Genetics Lab, Policlinico S. Orsola.Malpighi
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jul 30, 2018)
inheritedclinical testing

SCV004295200Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(May 20, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
Caucasianinheritedyes31not providednot providednot providedclinical testing

Citations

PubMed

Syndromic intellectual disability: a new phenotype caused by an aromatic amino acid decarboxylase gene (DDC) variant.

Graziano C, Wischmeijer A, Pippucci T, Fusco C, Diquigiovanni C, Nõukas M, Sauk M, Kurg A, Rivieri F, Blau N, Hoffmann GF, Chaubey A, Schwartz CE, Romeo G, Bonora E, Garavelli L, Seri M.

Gene. 2015 Apr 1;559(2):144-8. doi: 10.1016/j.gene.2015.01.026. Epub 2015 Jan 14.

PubMed [citation]
PMID:
25597765

New variants of AADC deficiency expand the knowledge of enzymatic phenotypes.

Montioli R, Bisello G, Dindo M, Rossignoli G, Voltattorni CB, Bertoldi M.

Arch Biochem Biophys. 2020 Mar 30;682:108263. doi: 10.1016/j.abb.2020.108263. Epub 2020 Jan 15.

PubMed [citation]
PMID:
31953134
See all PubMed Citations (3)

Details of each submission

From Medical Genetics Lab, Policlinico S. Orsola.Malpighi, SCV000788355.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Caucasian3not providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot provided3not provided1not provided

From Invitae, SCV004295200.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 20, 2024