NM_001082971.2(DDC):c.1040G>A (p.Arg347Gln) AND Deficiency of aromatic-L-amino-acid decarboxylase

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Oct 16, 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:: RCV000184027.17

Allele description [Variation Report for NM_001082971.2(DDC):c.1040G>A (p.Arg347Gln)]

NM_001082971.2(DDC):c.1040G>A (p.Arg347Gln)

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.1040G>A (p.Arg347Gln)

HGVS:

NC_000007.14:g.50476625C>T
NG_008742.1:g.93832G>A
NM_000790.4:c.1040G>A
NM_001082971.2:c.1040G>AMANE SELECT
NM_001242886.2:c.926G>A
NM_001242887.2:c.896G>A
NM_001242888.2:c.806G>A
NM_001242889.2:c.761G>A
NP_000781.2:p.Arg347Gln
NP_001076440.2:p.Arg347Gln
NP_001229815.2:p.Arg309Gln
NP_001229816.2:p.Arg299Gln
NP_001229817.2:p.Arg269Gln
NP_001229818.2:p.Arg254Gln
NC_000007.13:g.50544323C>T
NM_000790.3:c.1040G>A
NM_001082971.2:c.1040G>A
P20711:p.Arg347Gln

Protein change:

R254Q

Links:

UniProtKB: P20711#VAR_046143; dbSNP: rs201951824

NCBI 1000 Genomes Browser:

rs201951824

Molecular consequence:

NM_000790.4:c.1040G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001082971.2:c.1040G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001242886.2:c.926G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001242887.2:c.896G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001242888.2:c.806G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001242889.2:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000236558	Mendelics	no assertion criteria provided	Pathogenic (Aug 28, 2013)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20505134, 15079002, 17240182
SCV001424401	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001983524	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 15, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28924877, 30144970, 29356298, 17240182 Citation Link,
SCV002018152	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002061261	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26994895, 24865461, 30144970, 30952622, 25741868
SCV002230192	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 16, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17240182, 23430870, 30144970, 28492532
SCV002556698	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003835548	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency.

Brun L, Ngu LH, Keng WT, Ch'ng GS, Choy YS, Hwu WL, Lee WT, Willemsen MA, Verbeek MM, Wassenberg T, Régal L, Orcesi S, Tonduti D, Accorsi P, Testard H, Abdenur JE, Tay S, Allen GF, Heales S, Kern I, Kato M, Burlina A, et al.

Neurology. 2010 Jul 6;75(1):64-71. doi: 10.1212/WNL.0b013e3181e620ae. Epub 2010 May 26. Erratum in: Neurology. 2010 Aug 10;75(6):576. Dosage error in article text.

PubMed [citation]

PMID:: 20505134

Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis.

Pons R, Ford B, Chiriboga CA, Clayton PT, Hinton V, Hyland K, Sharma R, De Vivo DC.

Neurology. 2004 Apr 13;62(7):1058-65. Review.

PubMed [citation]

PMID:: 15079002

See all PubMed Citations (12)

Details of each submission

From Mendelics, SCV000236558.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

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

From Centogene AG - the Rare Disease Company, SCV001424401.1

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

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001983524.1

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

Description

Variant summary: DDC c.1040G>A (p.Arg347Gln) results in a conservative amino acid change located in the Pyridoxal phosphate-dependent transferase, major domain (IPR015421) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249548 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DDC causing Deficiency Of Aromatic-L-Amino-Acid Decarboxylase (4.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.1040G>A has been reported in the literature in multiple individuals affected with Deficiency Of Aromatic-L-Amino-Acid Decarboxylase (example Veerbeek_2007, Kuster_2018, Dai_2019). 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. The most pronounced variant effect results in <10% of normal decarboxylase activity towards L-Dopa substrate as observed by decreased steady state enzyme kinetic parameters (example, Montoli_2018). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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

From Revvity Omics, Revvity, SCV002018152.3

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

#	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

From DASA, SCV002061261.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

The c.1040G>A;p.(Arg347Gln) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 202181; PMID: 26994895; 24865461; 30144970; 30952622) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 24865461) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Pyridoxal_deC) - PM1. The variant is present at low allele frequencies population databases (rs201951824– gnomAD 0.0002629%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (PMID: 26994895) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 30144970) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002230192.3

#	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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 347 of the DDC protein (p.Arg347Gln). This variant is present in population databases (rs201951824, gnomAD 0.01%). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 17240182, 23430870, 30144970). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 202181). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.

#	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

From Genetics and Molecular Pathology, SA Pathology, SCV002556698.2

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

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

From Baylor Genetics, SCV003835548.1

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

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

Last Updated: Sep 29, 2024

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