Published functional studies demonstrate a damaging effect; specifically, the R418W variant revealed significant increase in intracellular cAMP and adenylyl cyclase activity, as compared to wild type, consistent with a gain-of-function effect (Chen et al., 2014; Doyle et al., 2019).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24700542, 25790160, 26537056, 30772269, 31422281, 29996192, 31628766, 32713175, 26085604, 27052971, 26686870, 29473048, 28511835, 28849312, 30345538, 33426171, 33827957, 33098801)
NM_183357.3(ADCY5):c.1252C>T (p.Arg418Trp)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
Pathogenic (11)
Pathogenic (11)
11 out of 17 submissions contributed to this classification
Help
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.
17
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_183357.3(ADCY5):c.1252C>T (p.Arg418Trp)
Variation ID: 162090 Accession: VCV000162090.75
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q21.1 3: 123352464 (GRCh38) [ NCBI UCSC ] 3: 123071311 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 27, 2026 Jan 1, 2026 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_183357.3:c.1252C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_899200.1:p.Arg418Trp missense NM_001199642.1:c.202C>T NP_001186571.1:p.Arg68Trp missense NM_001378259.1:c.1252C>T NP_001365188.1:p.Arg418Trp missense NC_000003.12:g.123352464G>A NC_000003.11:g.123071311G>A NG_033882.1:g.101082C>T O95622:p.Arg418Trp - Protein change
- R418W, R68W
- Other names
- -
- Canonical SPDI
- NC_000003.12:123352463:G:A
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
Help
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. |
|||
| ADCY5 | - | - |
GRCh38 GRCh37 |
967 | 997 | |
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Oct 26, 2025 | RCV000202545.38 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2026 | RCV000255111.60 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 11, 2016 | RCV000622463.11 |
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. |
Expand all rows
Collapse all rows
Help
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 25, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000321384.10
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
show
Published functional studies demonstrate a damaging effect; specifically, the R418W variant revealed significant increase in intracellular cAMP and adenylyl cyclase activity, as compared to wild type, consistent with a gain-of-function effect (Chen et al., 2014; Doyle et al., 2019).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24700542, 25790160, 26537056, 30772269, 31422281, 29996192, 31628766, 32713175, 26085604, 27052971, 26686870, 29473048, 28511835, 28849312, 30345538, 33426171, 33827957, 33098801) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jan 23, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Dyskinesia with orofacial involvement, autosomal dominant
(Autosomal dominant inheritance)
|
Institute of Human Genetics Munich, TUM University Hospital
Accession: SCV001150000.6
First in ClinVar: Feb 03, 2020 Last updated: Sep 22, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present) , Generalized dystonia (present) , Paroxysmal dystonia (present)
|
|
|
Pathogenic
(Apr 14, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002231327.5
First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026 |
Comment:
show
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 418 of the ADCY5 protein (p.Arg418Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ADCY5-related dyskinesia (PMID: 24700542, 26085604). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 162090). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ADCY5 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ADCY5 function (PMID: 24700542). For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jan 01, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250026.39
First in ClinVar: May 12, 2020 Last updated: Jul 27, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 7
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Dyskinesia with orofacial involvement, autosomal dominant |
Baylor Genetics
Accession: SCV000807307.3
First in ClinVar: Jun 14, 2017 Last updated: Mar 18, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Oct 11, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Inborn genetic diseases |
Ambry Genetics
Accession: SCV000741862.4
First in ClinVar: Apr 15, 2018 Last updated: Apr 13, 2025 |
Observation:
6
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Movement disorder (present) , Dystonia (present) , Chorea (present) , Dyskinesia (present) , Craniofacial dystonia (present) , Delayed gross motor development (present) , Speech articulation difficulties (present) , Gait disturbance (present) , Back pain (present) , Photophobia (present) , Headache (present) , Bilateral ptosis (present) , Toe walking (present) , Flexion contracture (present) , Smooth philtrum (present) , Thin upper lip vermilion (present) , Gestational diabetes (present)
Sex: male
Ethnicity/Population group: Caucasian
Observation 2
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Delayed fine motor development (present) , Gait ataxia (present) , Delayed speech and language development (present) , Dolichocephaly (present) , Myopathic facies (present) , Anxiety (present) , Delayed gross motor development (present) , Narrow face (present)
Sex: male
Ethnicity/Population group: Caucasian
Observation 3
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Hispanic/Mexican
Observation 4
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Movement disorder (present) , Intellectual disability (present) , Clonus (present) , Brisk reflexes (present) , Tongue fasciculations (present) , Sacral dimple (present) , Drooling (present) , Macrocephalus (present) , Spasticity (present) , Global developmental delay (present)
Sex: female
Ethnicity/Population group: Caucasian/German/Irish/French/Norwegian/Swedish
Observation 5
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Cerebral palsy (present) , Dystonia (present) , Chorea (present) , Hyporeflexia (present) , Muscular hypotonia (present)
Sex: female
Observation 6
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Involuntary movements (present) , Dystonia (present) , Dyskinesia (present) , Muscular hypotonia (present)
Sex: male
Ethnicity/Population group: Asian
|
|
|
Pathogenic
(Dec 15, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Dyskinesia with orofacial involvement, autosomal dominant |
Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute
Study: IDIOM
Accession: SCV000257554.2 First in ClinVar: Dec 21, 2015 Last updated: Dec 21, 2015 |
Observation 1
Collection method: research
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 2
Clinical Features:
Dyskinesia (present) , Facial myokymia (present) , Central hypotonia (present) , Upper limb hypertonia (present) , Dysarthria (present) , Hyperreflexia (present)
Family history: yes
Platform type: next-gen sequencing
|
|
|
Pathogenic
(Jul 25, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Dyskinesia with orofacial involvement, autosomal dominant |
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428868.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 02, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Dyskinesia with orofacial involvement, autosomal dominant
(Autosomal dominant inheritance)
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV005400027.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
show
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with autosomal recessive dyskinesia with orofacial involvement (MIM#619647) and autosomal dominant dyskinesia with orofacial involvement (MIM#606703), respectively. Loss of function is the likely mechanism of neurodevelopmental disorder with hyperkinetic movements and dyskinesia (PMID: 28971144, PMID: 30975617). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0254 - This variant is confirmed mosaic. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated AC_N domain (NCBI conserved domain). (I) 0703 - Other variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These alternative changes (p.(Arg418Gln), p.(Arg418Gly), p.Arg418Thr)) have been previously reported (ClinVar, PMID: 28511835, PMID: 28442302). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and de novo in individuals with childhood onset involuntary paroxysmal choreiform and dystonic movements. In one individual, the variant was mosaic (ClinVar, PMID: 24700542, PMID: 28511835, PMID: 32713175). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function, demonstrating increased adenyl cyclase activity compared to wildtype controls (PMID: 24700542). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Oct 23, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided
(Autosomal dominant inheritance)
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446730.2
First in ClinVar: Nov 28, 2020 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Ataxia (present) , Gait disturbance (present) , Dystonic disorder (present) , Hyperkinetic movements (present)
Sex: female
|
|
|
Pathogenic
(Oct 26, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Dyskinesia with orofacial involvement, autosomal dominant |
3billion
Accession: SCV005903650.3
First in ClinVar: Apr 13, 2025 Last updated: Jun 20, 2026 |
Comment:
show
The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24700542, 30772269). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000162090 /PMID: 24700542 /3billion dataset). Different missense changes at the same codon (p.Arg418Gln, p.Arg418Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000218354, VCV001722770 /PMID: 26537056, 27061943 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Platform type: exome sequencing
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Study: VKGL Data-share Consensus
Accession: SCV001954112.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Apr 01, 2014)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
DYSKINESIA WITH OROFACIAL INVOLVEMENT, AUTOSOMAL DOMINANT |
OMIM
Accession: SCV000579330.5
First in ClinVar: Jun 09, 2017 Last updated: Aug 15, 2022 |
Observation: 1
Collection method: literature only
Allele origin: unknown
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: unknown
Affected status: not provided
Comment on evidence:
In 2 unrelated teenaged girls of European ancestry with autosomal dominant dyskinesia with orofacial involvement (DSKOD; 606703), Chen et al. (2014) identified a de novo … (more)
In 2 unrelated teenaged girls of European ancestry with autosomal dominant dyskinesia with orofacial involvement (DSKOD; 606703), Chen et al. (2014) identified a de novo heterozygous c.1252C-T transition in the ADCY5 gene, resulting in an arg418-to-trp (R418W) substitution at a conserved residue in the sixth helical segment of the first transmembrane domain. The mutations were found by whole-exome sequencing. In vitro functional expression studies showed that mutant R418W ADCY5 caused a significant increase in cAMP production in response to beta-adrenergic stimulation compared to wildtype, consistent with a gain of function. In 2 unrelated patients of UK and Pakistani ancestry with DSKOD, Mencacci et al. (2015) identified a heterozygous R418W mutation. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In the first family, the mutation was inherited from the patient's mildly affected father who was somatic mosaic for the mutation. R418W occurred de novo in the proband from family 2. Functional studies of the variant were not performed. The probands had typical features of the disorder with onset of progressive and severe choreodystonic dyskinesias with orofacial involvement in the first years of life. The hyperkinetic movements were exacerbated by action, excitement, stress, and fatigue. Shetty et al. (2020) reported an Indian man with DKSOD who had the R418W mutation (c.1252C-T, NM_183357.2) in mosaic state with low mutant read depth. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was absent in the parents. The patient had paroxysmal involuntary movements during sleep. (less)
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Dyskinesia with orofacial involvement, autosomal dominant |
Genomics England Pilot Project, Genomics England
Accession: SCV001760103.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001806939.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744285.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
Dyskinesia with orofacial involvement, autosomal dominant |
GeneReviews
Accession: SCV000196147.2
First in ClinVar: Dec 21, 2015 Last updated: Oct 01, 2022 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: yes
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: yes
|
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 418 of the ADCY5 protein (p.Arg418Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ADCY5-related dyskinesia (PMID: 24700542, 26085604). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 162090). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ADCY5 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ADCY5 function (PMID: 24700542). For these reasons, this variant has been classified as Pathogenic.
Comment:
ADCY5: PM2, PM5, PM6, PS4:Moderate, PP2, PP3
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with autosomal recessive dyskinesia with orofacial involvement (MIM#619647) and autosomal dominant dyskinesia with orofacial involvement (MIM#606703), respectively. Loss of function is the likely mechanism of neurodevelopmental disorder with hyperkinetic movements and dyskinesia (PMID: 28971144, PMID: 30975617). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0254 - This variant is confirmed mosaic. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated AC_N domain (NCBI conserved domain). (I) 0703 - Other variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These alternative changes (p.(Arg418Gln), p.(Arg418Gly), p.Arg418Thr)) have been previously reported (ClinVar, PMID: 28511835, PMID: 28442302). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and de novo in individuals with childhood onset involuntary paroxysmal choreiform and dystonic movements. In one individual, the variant was mosaic (ClinVar, PMID: 24700542, PMID: 28511835, PMID: 32713175). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function, demonstrating increased adenyl cyclase activity compared to wildtype controls (PMID: 24700542). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24700542, 30772269). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000162090 /PMID: 24700542 /3billion dataset). Different missense changes at the same codon (p.Arg418Gln, p.Arg418Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000218354, VCV001722770 /PMID: 26537056, 27061943 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| ADCY5-Related Movement Disorder. | Adam MP | - | 2025 | PMID: 25521004 |
| Recurrent ADCY5 Mutation in Mosaic Form with Nocturnal Paroxysmal Dyskinesias and Video Electroencephalography Documentation of Dramatic Response to Caffeine Treatment. | Shetty K | Journal of movement disorders | 2020 | PMID: 32713175 |
| Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders. | Bohlega SA | Parkinsonism & related disorders | 2019 | PMID: 30975617 |
| Functional characterization of AC5 gain-of-function variants: Impact on the molecular basis of ADCY5-related dyskinesia. | Doyle TB | Biochemical pharmacology | 2019 | PMID: 30772269 |
| Autosomal recessive inheritance of ADCY5-related generalized dystonia and myoclonus. | Barrett MJ | Neurology. Genetics | 2017 | PMID: 28971144 |
| ADCY5-related movement disorders: Frequency, disease course and phenotypic variability in a cohort of paediatric patients. | Carecchio M | Parkinsonism & related disorders | 2017 | PMID: 28511835 |
| Facial twitches in ADCY5-associated disease - Myokymia or myoclonus? An electromyography study. | Tunc S | Parkinsonism & related disorders | 2017 | PMID: 28442302 |
| Phenotypic insights into ADCY5-associated disease. | Chang FC | Movement disorders : official journal of the Movement Disorder Society | 2016 | PMID: 27061943 |
| ADCY5 mutation carriers display pleiotropic paroxysmal day and nighttime dyskinesias. | Friedman JR | Movement disorders : official journal of the Movement Disorder Society | 2016 | PMID: 26686870 |
| 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 |
| A genome sequencing program for novel undiagnosed diseases. | Bloss CS | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25790160 |
| Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia. | Chen YZ | Annals of neurology | 2014 | PMID: 24700542 |
| Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder. | Fernandez M | Annals of neurology | 2001 | PMID: 11310626 |
| click to load more citations click to collapse | ||||
Text-mined citations for rs864309483 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 05, 2026
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.