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NM_183357.3(ADCY5):c.1253G>A (p.Arg418Gln) AND not provided

Germline classification:
Pathogenic (6 submissions)
Last evaluated:
Sep 16, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000494073.33

Allele description [Variation Report for NM_183357.3(ADCY5):c.1253G>A (p.Arg418Gln)]

NM_183357.3(ADCY5):c.1253G>A (p.Arg418Gln)

Gene:
ADCY5:adenylate cyclase 5 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3q21.1
Genomic location:
Preferred name:
NM_183357.3(ADCY5):c.1253G>A (p.Arg418Gln)
HGVS:
  • NC_000003.12:g.123352463C>T
  • NG_033882.1:g.101083G>A
  • NM_001199642.1:c.203G>A
  • NM_001378259.1:c.1253G>A
  • NM_183357.3:c.1253G>AMANE SELECT
  • NP_001186571.1:p.Arg68Gln
  • NP_001365188.1:p.Arg418Gln
  • NP_899200.1:p.Arg418Gln
  • NP_899200.1:p.Arg418Gln
  • NP_899200.1:p.Arg418Gln
  • NC_000003.11:g.123071310C>T
  • NM_183357.2:c.1253G>A
Protein change:
R418Q
Links:
dbSNP: rs864309515
NCBI 1000 Genomes Browser:
rs864309515
Molecular consequence:
  • NM_001199642.1:c.203G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378259.1:c.1253G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_183357.3:c.1253G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
5

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000582577GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Sep 16, 2023)
germlineclinical testing

Citation Link,

SCV001250025CeGaT Center for Human Genetics Tuebingen
criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)
Pathogenic
(Feb 1, 2021)
germlineclinical testing

Citation Link,

SCV001740128Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus
no assertion criteria provided
Pathogenicgermlineclinical testing

SCV001959467Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided
Pathogenicgermlineclinical testing

SCV001971789Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided
Pathogenicgermlineclinical testing

SCV002242132Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(May 15, 2023)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes5not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia.

Chen YZ, Friedman JR, Chen DH, Chan GC, Bloss CS, Hisama FM, Topol SE, Carson AR, Pham PH, Bonkowski ES, Scott ER, Lee JK, Zhang G, Oliveira G, Xu J, Scott-Van Zeeland AA, Chen Q, Levy S, Topol EJ, Storm D, Swanson PD, Bird TD, et al.

Ann Neurol. 2014 Apr;75(4):542-9. doi: 10.1002/ana.24119. Epub 2014 Mar 13.

PubMed [citation]
PMID:
24700542
PMCID:
PMC4457323

ADCY5 mutations are another cause of benign hereditary chorea.

Mencacci NE, Erro R, Wiethoff S, Hersheson J, Ryten M, Balint B, Ganos C, Stamelou M, Quinn N, Houlden H, Wood NW, Bhatia KP.

Neurology. 2015 Jul 7;85(1):80-8. doi: 10.1212/WNL.0000000000001720. Epub 2015 Jun 17.

PubMed [citation]
PMID:
26085604
PMCID:
PMC4501937
See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000582577.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From CeGaT Center for Human Genetics Tuebingen, SCV001250025.21

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided5not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided5not providednot providednot provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001740128.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001959467.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001971789.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV002242132.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 9, 2024