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NM_001082971.2(DDC):c.1234C>T (p.Arg412Trp) AND Deficiency of aromatic-L-amino-acid decarboxylase

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Mar 11, 2024
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:
RCV001380420.10

Allele description [Variation Report for NM_001082971.2(DDC):c.1234C>T (p.Arg412Trp)]

NM_001082971.2(DDC):c.1234C>T (p.Arg412Trp)

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.1234C>T (p.Arg412Trp)
HGVS:
  • NC_000007.14:g.50467222G>A
  • NG_008742.1:g.103235C>T
  • NM_000790.3:c.1234C>T
  • NM_000790.4:c.1234C>T
  • NM_001082971.2:c.1234C>TMANE SELECT
  • NM_001242886.2:c.1120C>T
  • NM_001242887.2:c.1090C>T
  • NM_001242888.2:c.1000C>T
  • NM_001242889.2:c.955C>T
  • NP_000781.2:p.Arg412Trp
  • NP_001076440.2:p.Arg412Trp
  • NP_001229815.2:p.Arg374Trp
  • NP_001229816.2:p.Arg364Trp
  • NP_001229817.2:p.Arg334Trp
  • NP_001229818.2:p.Arg319Trp
  • NC_000007.13:g.50534920G>A
  • NM_000790.4:c.1234C>T
Protein change:
R319W
Links:
dbSNP: rs542063660
NCBI 1000 Genomes Browser:
rs542063660
Molecular consequence:
  • NM_000790.4:c.1234C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001082971.2:c.1234C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242886.2:c.1120C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242887.2:c.1090C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242888.2:c.1000C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001242889.2:c.955C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001578489Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Aug 25, 2023)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV003927888Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
no assertion criteria provided
Likely pathogenic
(Apr 1, 2023)
germlineclinical testing

SCV005039573Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Mar 11, 2024)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Aromatic L-amino acid decarboxylase deficiency in Taiwan.

Lee HF, Tsai CR, Chi CS, Chang TM, Lee HJ.

Eur J Paediatr Neurol. 2009 Mar;13(2):135-40. doi: 10.1016/j.ejpn.2008.03.008. Epub 2008 Jun 24.

PubMed [citation]
PMID:
18567514

Natural History of Aromatic L-Amino Acid Decarboxylase Deficiency in Taiwan.

Hwu WL, Chien YH, Lee NC, Li MH.

JIMD Rep. 2018;40:1-6. doi: 10.1007/8904_2017_54. Epub 2017 Aug 31.

PubMed [citation]
PMID:
28856607
PMCID:
PMC6122029
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001578489.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects DDC function (PMID: 24865461). 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: 1068764). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 18567514, 28856607, 31975548). This variant is present in population databases (rs542063660, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 412 of the DDC protein (p.Arg412Trp).

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

From Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), SCV003927888.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005039573.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: DDC c.1234C>T (p.Arg412Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251426 control chromosomes (gnomAD). c.1234C>T has been reported in the literature in multiple individuals affected with Deficiency Of Aromatic-L-Amino-Acid Decarboxylase (e.g. Wen_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Montioli_2014), finding that the variant results in <10% of normal decarboxylase activity. The following publications have been ascertained in the context of this evaluation (PMID: 32409695, 24865461). ClinVar contains an entry for this variant (Variation ID: 1068764). Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Jul 7, 2024