NM_001082971.2(DDC):c.265A>G (p.Met89Val) AND Deficiency of aromatic-L-amino-acid decarboxylase

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 9, 2022
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:: RCV000339933.9

Allele description [Variation Report for NM_001082971.2(DDC):c.265A>G (p.Met89Val)]

NM_001082971.2(DDC):c.265A>G (p.Met89Val)

Genes:

DDC-AS1:DDC antisense RNA 1 [Gene - HGNC]
DDC:dopa decarboxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p12.1

Genomic location:

Preferred name:

NM_001082971.2(DDC):c.265A>G (p.Met89Val)

HGVS:

NC_000007.14:g.50539965T>C
NG_008742.1:g.30492A>G
NM_000790.4:c.265A>G
NM_001082971.2:c.265A>GMANE SELECT
NM_001242886.2:c.202-1986A>G
NM_001242887.2:c.265A>G
NM_001242888.2:c.201+3920A>G
NM_001242889.2:c.265A>G
NM_001242890.2:c.265A>G
NP_000781.2:p.Met89Val
NP_001076440.2:p.Met89Val
NP_001229816.2:p.Met89Val
NP_001229818.2:p.Met89Val
NP_001229819.2:p.Met89Val
NC_000007.13:g.50607663T>C
NM_000790.3:c.265A>G
NR_033845.1:n.313T>C

Protein change:

M89V

Links:

dbSNP: rs886062376

NCBI 1000 Genomes Browser:

rs886062376

Molecular consequence:

NM_001242886.2:c.202-1986A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001242888.2:c.201+3920A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000790.4:c.265A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001082971.2:c.265A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001242887.2:c.265A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001242889.2:c.265A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001242890.2:c.265A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_033845.1:n.313T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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

Recent activity

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PREDICTED: Rattus norvegicus tRNA methyltransferase 44 (Trmt44), transcript vari...
PREDICTED: Rattus norvegicus tRNA methyltransferase 44 (Trmt44), transcript variant X1, mRNA
gi|2678895129|ref|XM_039091963.2|

Nucleotide
cytochrome c oxidase subunit III (mitochondrion) [Pyrrhula pyrrhula]
cytochrome c oxidase subunit III (mitochondrion) [Pyrrhula pyrrhula]
gi|722491109|ref|YP_009108024.1|

Protein
Homo sapiens long intergenic non-protein coding RNA 529 (LINC00529), long non-co...
Homo sapiens long intergenic non-protein coding RNA 529 (LINC00529), long non-coding RNA
gi|1900697200|ref|NR_170283.1|

Nucleotide
cytochrome oxidase subunit 1, partial (mitochondrion) [Ancistrocerus albophalera...
cytochrome oxidase subunit 1, partial (mitochondrion) [Ancistrocerus albophaleratus]
gi|1068943541|gb|AOR15390.1|

Protein
MOB kinase activator 2 isoform X4 [Rattus norvegicus]
MOB kinase activator 2 isoform X4 [Rattus norvegicus]
gi|1958648821|ref|XP_038943802.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000469605	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV002148963	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 9, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000469605

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV002148963

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 9, 2022)

germline

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000469605.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002148963.3

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 360440). This variant has not been reported in the literature in individuals affected with DDC-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 89 of the DDC protein (p.Met89Val).

#	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: Sep 29, 2024

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