VCV000162091.36 - ClinVar

NM_183357.3(ADCY5):c.2176G>A (p.Ala726Thr)

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.

(9)

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.2176G>A (p.Ala726Thr)

Variation ID: 162091 Accession: VCV000162091.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q21.1 3: 123319754 (GRCh38) [ NCBI UCSC ] 3: 123038601 (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	Oct 11, 2015	Oct 20, 2024	Oct 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_183357.3:c.2176G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_899200.1:p.Ala726Thr	missense
NM_001199642.1:c.1126G>A	NP_001186571.1:p.Ala376Thr	missense
NM_001378259.1:c.2176G>A	NP_001365188.1:p.Ala726Thr	missense
NC_000003.12:g.123319754C>T
NC_000003.11:g.123038601C>T
NG_033882.1:g.133792G>A
	O95622:p.Ala726Thr

... more HGVS ... less HGVS

Protein change

A726T, A376T

Other names

Canonical SPDI

NC_000003.12:123319753:C:T

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: CA342901 UniProtKB: O95622#VAR_068821 OMIM: 600293.0001 dbSNP: rs796065306 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 (3)	criteria provided, single submitter	Dec 22, 2022	RCV000030679.15
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Oct 15, 2023	RCV000484892.38

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 (Mar 22, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568646.5 First in ClinVar: Apr 27, 2017 Last updated: Apr 01, 2023	Comment: Published functional studies demonstrate a damaging effect; specifically, mutant constructs stimulated with a beta-receptor agonist showed in a significant increase in cAMP levels compared to … (more) Published functional studies demonstrate a damaging effect; specifically, mutant constructs stimulated with a beta-receptor agonist showed in a significant increase in cAMP levels compared to wild-type cells, suggesting a gain-of-function effect (Chen et al., 2014); 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: 30772269, 22782511, 32627162, 24700542) (less)
Pathogenic (Sep 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: SCV001962517.20 First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Dec 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dyskinesia with orofacial involvement, autosomal dominant Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003808095.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PP1 strong, PP2 supporting, PP3 supporting Number of individuals with the variant: 1 Clinical Features: Hand tremor (present) , Dysmetria (present) , Gait ataxia (present) , Cerebellar ataxia (present) , Generalized hypotonia (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Mar 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022298.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 15, 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: SCV003525265.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 22782511‚ 32627162‚ 30772269 Comment: This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 726 of the ADCY5 protein (p.Ala726Thr). … (more) This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 726 of the ADCY5 protein (p.Ala726Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant ADCY5-related conditions (PMID: 22782511, 32627162). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1126G>A, p.A376T. ClinVar contains an entry for this variant (Variation ID: 162091). 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. Experimental studies have shown that this missense change affects ADCY5 function (PMID: 30772269). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 08, 2015)	no assertion criteria provided Method: literature only	DYSKINESIA WITH OROFACIAL INVOLVEMENT, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000053340.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 12, 2021	Publications: PubMed (8) PubMed: 152174‚ 11310626‚ 22782511‚ 16537460‚ 24700542‚ 1003446‚ 11445636‚ 26537056 Comment on evidence: In affected members of a large multigenerational German family with autosomal dominant dyskinesia with orofacial involvement (DSKOD; 606703), previously reported by Bird and Hall (1978) … (more) In affected members of a large multigenerational German family with autosomal dominant dyskinesia with orofacial involvement (DSKOD; 606703), previously reported by Bird and Hall (1978) and Fernandez et al. (2001), Chen et al. (2012) identified a heterozygous c.2176G-A transition in exon 10 of the ADCY5 gene, resulting in an ala726-to-thr (A726T) substitution at a highly conserved residue between the first intracellular cyclase homology domain and the second membrane-spanning domain. The mutation was identified by exome sequencing of 1 affected individual and was not found in 3,510 control exomes. Chen et al. (2012) noted that Adcy5-null mice develop a movement disorder that is worsened by stress (Kim et al., 2006), supporting the pathogenicity of the A726T mutation. In vitro functional expression studies performed by Chen et al. (2014) showed that mutant A726T ADCY5 caused a significant increase in cAMP production in response to beta-adrenergic stimulation compared to wildtype, consistent with a gain of function. In affected members of a large 5-generation family (EHC) with DSKOD, previously reported by Bird et al. (1976) and Fernandez et al. (2001), Chen et al. (2015) identified a heterozygous A726T mutation in the ADCY5 gene. The mutation, which was found by direct Sanger sequencing, segregated completely with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. Haplotype analysis showed that the German family reported by Chen et al. (2012) and family EHC, from the US, did not share a common haplotype; the mutations arose independently. The EHC family had originally been diagnosed with benign hereditary chorea (see 118700). Chen et al. (2015) noted that the A726T mutation is associated with a relatively mild phenotype. Fernandez et al. (2001) stated that the phenotype in this family was nonprogressive in adulthood and that dementia was not observed, although some patients had educational or behavioral difficulties, possibly resulting from social isolation. (less)
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: SCV002035016.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Likely 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: SCV002037245.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
not provided (-)	no classification provided Method: literature only	Dyskinesia with orofacial involvement, autosomal dominant Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000196148.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 24700542‚ 11310626 BookShelf: NBK263441 BookShelf: NBK263441

Comment:

Published functional studies demonstrate a damaging effect; specifically, mutant constructs stimulated with a beta-receptor agonist showed in a significant increase in cAMP levels compared to wild-type cells, suggesting a gain-of-function effect (Chen et al., 2014); 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: 30772269, 22782511, 32627162, 24700542)

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 726 of the ADCY5 protein (p.Ala726Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant ADCY5-related conditions (PMID: 22782511, 32627162). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1126G>A, p.A376T. ClinVar contains an entry for this variant (Variation ID: 162091). 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. Experimental studies have shown that this missense change affects ADCY5 function (PMID: 30772269). 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
[ADCY5-associated dyskinesia in young children: a case report of a family and an updated review].	Aguilera-Nieto L	Revista de neurologia	2020	PMID: 32627162
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 dyskinesia: Broader spectrum and genotype-phenotype correlations.	Chen DH	Neurology	2015	PMID: 26537056
Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia.	Chen YZ	Annals of neurology	2014	PMID: 24700542
Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylyl cyclase 5.	Chen YZ	Archives of neurology	2012	PMID: 22782511
Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action.	Kim KS	Proceedings of the National Academy of Sciences of the United States of America	2006	PMID: 16537460
Hereditary benign chorea: clinical and genetic features of a distinct disease.	Fernandez M	Neurology	2001	PMID: 11445636
Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder.	Fernandez M	Annals of neurology	2001	PMID: 11310626
Additional information on familial essential (benign) chorea.	Bird TD	Clinical genetics	1978	PMID: 152174
Familial essential ("benign") chorea.	Bird TD	Journal of medical genetics	1976	PMID: 1003446
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Text-mined citations for rs796065306 ...

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.2176G>A (p.Ala726Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs796065306 ...