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)
ClinVar Genomic variation as it relates to human health
NM_001080522.2(CC2D2A):c.3289delG
Germline
Classification
Help
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.
(19)
Help
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
19
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001080522.2(CC2D2A):c.3289delG
Variation ID: 56303 Accession: VCV000056303.60
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 4p15.32 4: 15567676 (GRCh38) [ NCBI UCSC ] 4: 15569299 (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 Jul 24, 2013 Dec 22, 2024 Jan 24, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001080522.2:c.3289-1del splice acceptor NM_001080522.2:c.3289delG splice acceptor NC_000004.12:g.15567677del NC_000004.11:g.15569300del NG_013035.1:g.102812del LRG_697:g.102812del LRG_697t1:c.3289del - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000004.12:15567675:GG:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
Unknown function
-
Global minor allele
frequency (GMAF) HelpThe 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
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| CC2D2A | - | - |
GRCh38 GRCh37 |
2067 | 2123 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV000049715.11 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 24, 2022 | RCV000201550.21 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jul 18, 2023 | RCV000727050.46 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 24, 2024 | RCV000817119.16 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 16, 2021 | RCV002227058.10 |
| Pathogenic (1) |
criteria provided, single submitter
|
May 11, 2022 | RCV002513687.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 12, 2024 | RCV004528259.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jan 1, 2010 | RCV002266895.8 |
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
(Dec 29, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000705167.2
First in ClinVar: Nov 09, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Pathogenic
(Jul 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001168531.5
First in ClinVar: Mar 16, 2020 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(Aug 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249102.27
First in ClinVar: May 12, 2020 Last updated: Dec 22, 2024 |
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Feb 23, 2015)
|
criteria provided, single submitter
Method: research
|
Joubert syndrome 9
Affected status: yes
Allele origin:
unknown
|
UW Hindbrain Malformation Research Program, University of Washington
Additional submitter:
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV000256334.1
First in ClinVar: Nov 09, 2015 Last updated: Nov 09, 2015 |
|
|
|
Pathogenic
(May 17, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Joubert syndrome 9
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000593889.1
First in ClinVar: Nov 09, 2015 Last updated: Nov 09, 2015 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Joubert syndrome 9
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia
Accession: SCV001424034.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
Zygosity: Compound Heterozygote
|
|
|
Pathogenic
(Oct 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Joubert syndrome 9
Affected status: yes
Allele origin:
maternal
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934273.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Comment:
This variant was identified as compound heterozygous with NM_001080522.2:c.4786G>A.
|
|
|
Pathogenic
(Dec 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV002506428.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Comment:
ACMG categories: PVS1,PM2,PM3,PP5
Number of individuals with the variant: 1
Clinical Features:
Encephalocele (present) , Renal cyst (present) , Oligohydramnios (present) , Ventricular septal defect (present)
Zygosity: Homozygote
|
|
|
Pathogenic
(Jul 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016952.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial aplasia of the vermis
Meckel-Gruber syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000957664.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(May 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003716176.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
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, … (more)
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. (less)
|
|
|
Pathogenic
(Jun 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Joubert syndrome 9
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557629.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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 (less)
|
|
|
probable-pathogenic
(-)
|
no assertion criteria provided
Method: not provided
|
Meckel syndrome, type 6
Affected status: not provided
Allele origin:
unknown
|
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082122.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
|
Comment:
Converted during submission to Likely pathogenic.
|
|
|
Pathogenic
(Jan 01, 2010)
|
no assertion criteria provided
Method: literature only
|
COACH SYNDROME 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020932.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 07, 2020 |
Comment on evidence:
In a 22-year-old woman (UW49) with features of Joubert syndrome and liver disease (COACH2; 619111), defined as Joubert syndrome with liver disease by Doherty et … (more)
In a 22-year-old woman (UW49) with features of Joubert syndrome and liver disease (COACH2; 619111), defined as Joubert syndrome with liver disease by Doherty et al. (2010), Gorden et al. (2008) identified compound heterozygosity for 2 mutations in the CC2D2A gene: a 1-bp deletion (3289delG), resulting in a frameshift and premature termination, and the R1528C mutation (612013.0004). The patient had agenesis of the corpus callosum, hydrocephalus, cerebellar vermis hypoplasia, abnormal eye movements, coloboma, mild renal disease, and hepatic fibrosis requiring liver transplant at age 10 years. Gorden et al. (2008) noted that the features in this patient were reminiscent of COACH syndrome, which in some cases may be a variant representing a transitional phenotype between Joubert syndrome and Meckel syndrome. Two additional sibs with Joubert syndrome without liver disease, renal fibrosis, or polydactyly were found to be heterozygous for the 3289delG mutation; however, a second mutation was not identified. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932832.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
|
|
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: SCV001808523.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 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: SCV001744820.3 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
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973251.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
|
Pathogenic
(Sep 12, 2024)
|
no assertion criteria provided
Method: clinical testing
|
CC2D2A-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004104021.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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: reported as p.V1097FfsX1 in Table 1, 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. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant was identified as compound heterozygous with NM_001080522.2:c.4786G>A.
Comment:
ACMG categories: PVS1,PM2,PM3,PP5
Comment:
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.
Comment:
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.
Comment:
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
Comment:
Converted during submission to Likely pathogenic.
Comment:
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: reported as p.V1097FfsX1 in Table 1, 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.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
Unknown function
|
Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia
Accession: SCV001424034.1
|
|
Comment:
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)
Comment:
This variant was identified as compound heterozygous with NM_001080522.2:c.4786G>A.
Comment:
ACMG categories: PVS1,PM2,PM3,PP5
Comment:
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.
Comment:
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.
Comment:
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
Comment:
Converted during submission to Likely pathogenic.
Comment:
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: reported as p.V1097FfsX1 in Table 1, 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center. | Vilboux T | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28125082 |
| Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. | Bachmann-Gagescu R | Journal of medical genetics | 2015 | PMID: 26092869 |
| Genotype-phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures. | Bachmann-Gagescu R | Journal of medical genetics | 2012 | PMID: 22241855 |
| Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). | Doherty D | Journal of medical genetics | 2010 | PMID: 19574260 |
| CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation. | Mougou-Zerelli S | Human mutation | 2009 | PMID: 19777577 |
| Mutation spectrum of Meckel syndrome genes: one group of syndromes or several distinct groups? | Tallila J | Human mutation | 2009 | PMID: 19466712 |
| CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. | Gorden NT | American journal of human genetics | 2008 | PMID: 18950740 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CC2D2A | - | - | - | - |
Text-mined citations for rs386833751 ...
HelpThese 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 Jan 13, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.