ClinVar Genomic variation as it relates to human health
NM_183357.3(ADCY5):c.1253G>A (p.Arg418Gln)
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_183357.3(ADCY5):c.1253G>A (p.Arg418Gln)
Variation ID: 218354 Accession: VCV000218354.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q21.1 3: 123352463 (GRCh38) [ NCBI UCSC ] 3: 123071310 (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 Dec 21, 2015 Aug 4, 2024 Sep 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_183357.3:c.1253G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_899200.1:p.Arg418Gln missense NM_001199642.1:c.203G>A NP_001186571.1:p.Arg68Gln missense NM_001378259.1:c.1253G>A NP_001365188.1:p.Arg418Gln missense NC_000003.12:g.123352463C>T NC_000003.11:g.123071310C>T NG_033882.1:g.101083G>A - Protein change
- R418Q, R68Q
- Other names
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- Canonical SPDI
- NC_000003.12:123352462:C: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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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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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ADCY5 | - | - |
GRCh38 GRCh37 |
756 | 784 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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 (4) |
criteria provided, multiple submitters, no conflicts
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Dec 30, 2022 | RCV000202572.18 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Sep 16, 2023 | RCV000494073.36 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002273986.9 | |
See cases
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Pathogenic (1) |
criteria provided, single submitter
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Nov 21, 2022 | RCV003128395.8 |
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
Help
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
Help
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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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental delay
Affected status: yes
Allele origin:
de novo
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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002558905.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
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Pathogenic
(Jun 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Dyskinesia with orofacial involvement, autosomal dominant
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764997.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present) , Chorea (present)
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Pathogenic
(Dec 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Dyskinesia with orofacial involvement, autosomal dominant
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV002775063.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Clinical Features:
Dysarthria (present) , Dystonic disorder (present) , Myoclonus (present) , Abnormal pyramidal sign (present) , Generalized dystonia (present)
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Pathogenic
(Nov 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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see cases
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV003804924.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG categories: PS1,PS4,PP5
Number of individuals with the variant: 1
Clinical Features:
Dyskinesia (present)
Age: 30-39 years
Sex: male
Tissue: blood
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Pathogenic
(Sep 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000582577.6
First in ClinVar: Jul 02, 2017 Last updated: Sep 22, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28442302, 27933653, 30772269, 31970214, 26686870, 28229249, 27931826, 29086067, 28511835, 29473048, 27061943, 30172639, 31737037, 35872528, 35002175, 26537056) (less)
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Pathogenic
(May 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002242132.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg418 amino acid residue in ADCY5. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg418 amino acid residue in ADCY5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24700542, 26085604). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ADCY5 function (PMID: 30772269). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADCY5 protein function. ClinVar contains an entry for this variant (Variation ID: 218354). This missense change has been observed in individual(s) with ADCY5-related conditions (PMID: 26537056, 28511835). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 418 of the ADCY5 protein (p.Arg418Gln). (less)
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Pathogenic
(Feb 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250025.24
First in ClinVar: May 12, 2020 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 5
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Dyskinesia with orofacial involvement, autosomal dominant
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV001787119.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Sex: female
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740128.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959467.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971789.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Dyskinesia with orofacial involvement, autosomal dominant
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000257543.2
First in ClinVar: Dec 21, 2015 Last updated: Oct 01, 2022 |
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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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ADCY5 Dyskinesia. | Adam MP | - | 2020 | PMID: 25521004 |
Functional characterization of AC5 gain-of-function variants: Impact on the molecular basis of ADCY5-related dyskinesia. | Doyle TB | Biochemical pharmacology | 2019 | PMID: 30772269 |
ADCY5-related movement disorders: Frequency, disease course and phenotypic variability in a cohort of paediatric patients. | Carecchio M | Parkinsonism & related disorders | 2017 | PMID: 28511835 |
ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations. | Chen DH | Neurology | 2015 | PMID: 26537056 |
ADCY5 mutations are another cause of benign hereditary chorea. | Mencacci NE | Neurology | 2015 | PMID: 26085604 |
Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia. | Chen YZ | Annals of neurology | 2014 | PMID: 24700542 |
Text-mined citations for rs864309515 ...
HelpRecord last updated Sep 08, 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.