ClinVar Genomic variation as it relates to human health
NM_001082971.2(DDC):c.140C>A (p.Pro47His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001082971.2(DDC):c.140C>A (p.Pro47His)
Variation ID: 2585327 Accession: VCV002585327.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p12.1 7: 50543946 (GRCh38) [ NCBI UCSC ] 7: 50611644 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 28, 2023 Feb 14, 2024 Jul 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001082971.2:c.140C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001076440.2:p.Pro47His missense NM_000790.4:c.140C>A NP_000781.2:p.Pro47His missense NM_001242886.2:c.140C>A NP_001229815.2:p.Pro47His missense NM_001242887.2:c.140C>A NP_001229816.2:p.Pro47His missense NM_001242888.2:c.140C>A NP_001229817.2:p.Pro47His missense NM_001242889.2:c.140C>A NP_001229818.2:p.Pro47His missense NM_001242890.2:c.140C>A NP_001229819.2:p.Pro47His missense NC_000007.14:g.50543946G>T NC_000007.13:g.50611644G>T NG_008742.1:g.26511C>A NG_008742.2:g.26459C>A - Protein change
- P47H
- Other names
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- Canonical SPDI
- NC_000007.14:50543945:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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DDC | - | - |
GRCh38 GRCh37 |
459 | 574 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 11, 2023 | RCV003337943.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of aromatic-L-amino-acid decarboxylase
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048393.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The c.140C>A (p.Pro47His) variant in DDC gene has been reported in homozygous state in individuals affected with aromatic L-amino acid decarboxylase (AADC) deficiency (Pons et … (more)
The c.140C>A (p.Pro47His) variant in DDC gene has been reported in homozygous state in individuals affected with aromatic L-amino acid decarboxylase (AADC) deficiency (Pons et al., 2004). The p.Pro47His variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid Pro at position 47 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Pro47His in DDC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Neck muscle weakness (present) , Rhizomelia (present) , Depressed nasal bridge (present) , Hypotonia (present) , Lethargy (present) , Cerebral … (more)
Global developmental delay (present) , Neck muscle weakness (present) , Rhizomelia (present) , Depressed nasal bridge (present) , Hypotonia (present) , Lethargy (present) , Cerebral atrophy (present) , Thin corpus callosum (present) , Abnormal brain morphology (present) , Abnormal facial shape (present) (less)
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Pathogenic
(Jul 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of aromatic-L-amino-acid decarboxylase
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004295204.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 47 of the DDC protein (p.Pro47His). … (more)
This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 47 of the DDC protein (p.Pro47His). This variant is present in population databases (rs780542462, gnomAD 0.006%). This missense change has been observed in individual(s) with aromatic L-amino acid decarboxylase deficiency (PMID: 15079002, 33996177). 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. Experimental studies have shown that this missense change affects DDC function (PMID: 24865461). For these reasons, this variant has been classified as Pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical Profile and Outcome of Indian Children with Aromatic L-Amino Acid Decarboxylase Deficiency: A primary CSF Neurotransmitter Disorder Mimicking as Dyskinetic Cerebral Palsy. | Gowda VK | Journal of pediatric genetics | 2021 | PMID: 33996177 |
A comprehensive picture of the mutations associated with aromatic amino acid decarboxylase deficiency: from molecular mechanisms to therapy implications. | Montioli R | Human molecular genetics | 2014 | PMID: 24865461 |
Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis. | Pons R | Neurology | 2004 | PMID: 15079002 |
Text-mined citations for this variant ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.