VCV000162090.57 - ClinVar

NM_183357.3(ADCY5):c.1252C>T (p.Arg418Trp)

Germline

Classification

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.

(15)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

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: VCV000162090.57

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	Oct 20, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

R418W, R68W

Other names

Canonical SPDI

NC_000003.12:123352463:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA347787 UniProtKB: O95622#VAR_073778 OMIM: 600293.0002 dbSNP: rs864309483 VarSome

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
Gene	OMIM	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	768	796

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.
Dyskinesia with orofacial involvement, autosomal dominant	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jun 13, 2019	RCV000202545.28
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000255111.44
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Oct 11, 2016	RCV000622463.10

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 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 (Jun 13, 2019)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Dyskinesia with orofacial involvement, autosomal dominant (Autosomal dominant inheritance) Affected status: yes Allele origin: germline, de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150000.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Observation 1: Sex: female Tissue: blood Observation 2: Sex: male Tissue: blood Observation 3: Sex: female Tissue: blood
Pathogenic (May 25, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321384.10 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dyskinesia with orofacial involvement, autosomal dominant Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000807307.3 First in ClinVar: Jun 14, 2017 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 25326635
Pathogenic (Feb 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250026.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 6
Pathogenic (Dec 15, 2015)	criteria provided, single submitter (STSI_classification_crtieria_for_IDIOM) Method: research	Dyskinesia with orofacial involvement, autosomal dominant Affected status: yes Allele origin: de novo	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	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
Pathogenic (Jul 25, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dyskinesia with orofacial involvement, autosomal dominant Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428868.1 First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020	Number of individuals with the variant: 1
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446730.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Cerebellar ataxia (present) , Gait disturbance (present) , Dystonic disorder (present) , Hyperkinetic movements (present) Sex: female
Pathogenic (Oct 11, 2016)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741862.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (7) PubMed: 25790160‚ 26686870‚ 24700542‚ 27061943‚ 26537056‚ 26085604‚ 28511835 Observation 1: 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 … (more) 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) (less) Sex: male Ethnicity/Population group: Caucasian Observation 2: 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 … (more) 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) (less) Sex: male Ethnicity/Population group: Caucasian Observation 3: Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: Hispanic/Mexican Observation 4: 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) … (more) 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) (less) Sex: female Ethnicity/Population group: Caucasian/German/Irish/French/Norwegian/Swedish Observation 5: 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: 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 01, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002231327.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 24700542‚ 26085604 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 … (more) 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). 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 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)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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
Pathogenic (Apr 01, 2014)	no assertion criteria provided Method: literature only	DYSKINESIA WITH OROFACIAL INVOLVEMENT, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000579330.5 First in ClinVar: Jun 09, 2017 Last updated: Aug 15, 2022	Publications: PubMed (3) PubMed: 24700542‚ 26085604‚ 32713175 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 (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Dyskinesia with orofacial involvement, autosomal dominant Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760103.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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: SCV001954112.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: literature only	Dyskinesia with orofacial involvement, autosomal dominant Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000196147.2 First in ClinVar: Dec 21, 2015 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 24700542‚ 11310626 BookShelf: NBK263441 BookShelf: NBK263441
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Comment:

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)

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). 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 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.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
ADCY5 Dyskinesia.	Adam MP	-	2020	PMID: 25521004
ADCY5-related movement disorders: Frequency, disease course and phenotypic variability in a cohort of paediatric patients.	Carecchio M	Parkinsonism & related disorders	2017	PMID: 28511835
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

Text-mined citations for rs864309483 ...

These 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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_183357.3(ADCY5):c.1252C>T (p.Arg418Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs864309483 ...