NM_001082971.2(DDC):c.446G>C (p.Ser149Thr) AND Deficiency of aromatic-L-amino-acid decarboxylase

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Apr 11, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000787964.7

Allele description [Variation Report for NM_001082971.2(DDC):c.446G>C (p.Ser149Thr)]

NM_001082971.2(DDC):c.446G>C (p.Ser149Thr)

Gene:

DDC:dopa decarboxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p12.1

Genomic location:

Preferred name:

NM_001082971.2(DDC):c.446G>C (p.Ser149Thr)

HGVS:

NC_000007.14:g.50529332C>G
NG_008742.1:g.41125G>C
NM_000790.4:c.446G>C
NM_001082971.2:c.446G>CMANE SELECT
NM_001242886.2:c.332G>C
NM_001242887.2:c.446G>C
NM_001242888.2:c.212G>C
NM_001242889.2:c.435+8528G>C
NM_001242890.2:c.446G>C
NP_000781.2:p.Ser149Thr
NP_001076440.2:p.Ser149Thr
NP_001229815.2:p.Ser111Thr
NP_001229816.2:p.Ser149Thr
NP_001229817.2:p.Ser71Thr
NP_001229819.2:p.Ser149Thr
NC_000007.13:g.50597030C>G
NM_000790.3:c.446G>C
p.S149T

Protein change:

S111T

Links:

dbSNP: rs971183744

NCBI 1000 Genomes Browser:

rs971183744

Molecular consequence:

NM_001242889.2:c.435+8528G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000790.4:c.446G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001082971.2:c.446G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001242886.2:c.332G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001242887.2:c.446G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001242888.2:c.212G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001242890.2:c.446G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Deficiency of aromatic-L-amino-acid decarboxylase
Synonyms:: AADC DEFICIENCY; DDC DEFICIENCY; DOPA DECARBOXYLASE DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012084; MedGen: C1291564; Orphanet: 35708; OMIM: 608643

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000926987	Undiagnosed Diseases Network, NIH	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2018)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003439963	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 11, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25001633, 31607746, 32369189, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000926987

Undiagnosed Diseases Network, NIH

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 3, 2018)

inherited

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003439963

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 11, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Mexican	inherited	yes	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Widening Phenotypic Spectrum of AADC Deficiency, a Disorder of Dopamine and Serotonin Synthesis.

Helman G, Pappa MB, Pearl PL.

JIMD Rep. 2014;17:23-7. doi: 10.1007/8904_2014_327. Epub 2014 Jul 8. Erratum in: JIMD Rep. 2014;17:97. doi: 10.1007/978-3-662-44578-5_344.

PubMed [citation]

PMID:: 25001633
PMCID:: PMC4241195

See all PubMed Citations (5)

Details of each submission

From Undiagnosed Diseases Network, NIH, SCV000926987.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Mexican	1	not provided	not provided	clinical testing (GTR000553916.1)	PubMed (1)

Description

The activity of aromatic L-amino acid decarboxylase (AADC) in plasma was below reference range of CLIA laboratory. This demonstrated the patient has AADC deficiency

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	blood	not provided	(GTR000553916.1)	1	not provided	1	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003439963.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 149 of the DDC protein (p.Ser149Thr). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of aromatic L-amino acid decarboxylase deficiency (PMID: 25001633, 31607746, 32369189). ClinVar contains an entry for this variant (Variation ID: 636255). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 19, 2025

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