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

dbSNP: rs864309515

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494073	SCV000582577	pathogenic	not provided	2023-09-16	criteria provided, single submitter	clinical testing	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)
CeGaT Center for Human Genetics Tuebingen	RCV000494073	SCV001250025	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000494073	SCV002242132	pathogenic	not provided	2024-08-29	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 218354). 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) has been performed 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). 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. For these reasons, this variant has been classified as Pathogenic.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273986	SCV002558905	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000202572	SCV002764997	pathogenic	Dyskinesia with orofacial involvement, autosomal dominant	2021-06-10	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000202572	SCV002775063	pathogenic	Dyskinesia with orofacial involvement, autosomal dominant	2022-12-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV003128395	SCV003804924	pathogenic	See cases	2022-11-21	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PS4,PP5
GeneReviews	RCV000202572	SCV000257543	not provided	Dyskinesia with orofacial involvement, autosomal dominant		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000494073	SCV001740128	pathogenic	not provided		no assertion criteria provided	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000202572	SCV001787119	likely pathogenic	Dyskinesia with orofacial involvement, autosomal dominant		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000494073	SCV001959467	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000494073	SCV001971789	pathogenic	not provided		no assertion criteria provided	clinical testing