Submissions for variant NM_001080522.2(CC2D2A):c.3289delG

dbSNP: rs386833751

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201550	SCV000256334	pathogenic	Joubert syndrome 9	2015-02-23	criteria provided, single submitter	research
Genetic Services Laboratory, University of Chicago	RCV000201550	SCV000593889	pathogenic	Joubert syndrome 9	2016-05-17	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727050	SCV000705167	pathogenic	not provided	2016-12-29	criteria provided, single submitter	clinical testing
Invitae	RCV000817119	SCV000957664	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val1097Phefs*2) in the CC2D2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CC2D2A are known to be pathogenic (PMID: 19777577). This variant is present in population databases (rs770470219, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with Joubert syndrome and Meckel syndrome (PMID: 18950740, 19466712, 22241855). ClinVar contains an entry for this variant (Variation ID: 56303). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000727050	SCV001168531	pathogenic	not provided	2022-07-27	criteria provided, single submitter	clinical testing	Identified in a patient with COACH syndrome who harbored a second variant on the opposite allele and in two siblings with Joubert syndrome who did not have a second identifiable variant (Gorden et al., 2008; Bachmann-Gagescu et al., 2012); Reported in trans with another CC2D2A variant in a family with Meckel syndrome (Tallila et al., 2009); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 18950740, 19466712, 19574260, 22241855, 26092869, 32488064, 33084218)
CeGaT Center for Human Genetics Tuebingen	RCV000727050	SCV001249102	pathogenic	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia	RCV000201550	SCV001424034	pathogenic	Joubert syndrome 9		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000201550	SCV001934273	pathogenic	Joubert syndrome 9	2020-10-27	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_001080522.2:c.4786G>A.
Revvity Omics, Revvity	RCV000727050	SCV002016952	pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV002227058	SCV002506428	pathogenic	See cases	2021-12-16	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PM3,PP5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000201550	SCV002557629	pathogenic	Joubert syndrome 9	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 9, (MIM#612285); Meckel syndrome 6 (MIM#612284) and COACH syndrome (MIM#216360). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 54 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least 10 individuals, two of whom diagnosed with Joubert Syndrome (ClinVar; PMID: 28125082). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV002513687	SCV003716176	pathogenic	Inborn genetic diseases	2022-05-11	criteria provided, single submitter	clinical testing	The c.3289delG (p.V1097Ffs*2) alteration, located in exon 27 (coding exon 25) of the CC2D2A gene, consists of a deletion of one nucleotide at position 3289, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been seen along with another CC2D2A alteration in multiple individuals with clinical features of CC2D2A-related ciliopathy (Doherty, 2010; Bachmann-Gagescu, 2012; Bachmann-Gagescu, 2015; Vilboux, 2017). Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398639	SCV004104021	pathogenic	CC2D2A-related condition	2023-12-13	criteria provided, single submitter	clinical testing	The CC2D2A c.3289delG variant is predicted to result in a frameshift and premature protein termination (p.Val1097Phefs*2). This variant has been reported in the compound heterozygous state in multiple individuals with Joubert syndrome and related disorders (see example: Gorden et al. 2008. PubMed ID: 18950740; Table S5, Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CC2D2A are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV002266895	SCV000020932	pathogenic	COACH syndrome 2	2010-01-01	no assertion criteria provided	literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049715	SCV000082122	probable-pathogenic	Meckel syndrome, type 6		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000727050	SCV001744820	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000727050	SCV001808523	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000727050	SCV001932832	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000727050	SCV001973251	pathogenic	not provided		no assertion criteria provided	clinical testing