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Intellectual disability
Gene: C2CD3

C2CD3 (C2 calcium dependent domain containing 3)
EnsemblGeneIds (GRCh38): ENSG00000168014
EnsemblGeneIds (GRCh37): ENSG00000168014
OMIM: 615944, Gene2Phenotype
C2CD3 is in 12 panels

7 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Despite phenotypic diversity among cases with C2CD3 variants, ID/DD is consistently reported in living patients.

Therefore, this gene could be promoted from Amber to Green at the next GMS panel update (added 'for-review' tag).
Created: 13 Oct 2020, 3:03 p.m. | Last Modified: 13 Oct 2020, 3:03 p.m.

Panel Version: 3.435

- PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function.

- PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B.

- PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases.

- PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly.

- PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease:
Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs.
Family 2: fetus with encephalocele and a ventricular septal defect. Similar abnormalities were identified in a sib (also a terminated fetus), but DNA analysis was not performed on the latter.
Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas.
Created: 13 Oct 2020, 2:03 p.m. | Last Modified: 13 Oct 2020, 2:05 p.m.

Panel Version: 3.432

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Orofaciodigital syndrome XIV, 615948; Joubert-related disorder

Publications

Created: 13 Oct 2020, 2:03 p.m.
Last Modified: 13 Oct 2020, 2:05 p.m.
Panel version: 3.432

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Six families reported with bi-allelic variants in this gene and a ciliopathy, ranging in severity, but generally including ID.
Created: 29 Jan 2020, 11:01 a.m. | Last Modified: 29 Jan 2020, 11:01 a.m.

Panel Version: 3.0

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Orofaciodigital syndrome XIV, MIM# 615948

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 29 Jan 2020, 11:01 a.m.
Last Modified: 29 Jan 2020, 11:01 a.m.
Panel version: 3.0

Louise Daugherty (Genomics England Curator)

Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Created: 29 Sep 2018, 9:26 p.m.

Created: 29 Sep 2018, 9:26 p.m.

Panel version: 2.486

Sarah Leigh (Genomics England Curator)

I don't know

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.

Panel Version: 3.1510

Associated with phenotype in OMIM and as a probable G2P. At least 3 variants reported in two cases of orofaciodigital syndrome XIV 615948 (one homozygous, one compound heterozygous). Two additional variants were reported in two sibling fetuses (terminations), with an overall defect in ciliogenesis resulting in a different clinical presentation, dominated by skeletal dysplasia with no microcephaly, clearly intellectual status could not be established
Created: 15 Dec 2017, 9:38 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

Created: 15 Dec 2017, 9:38 a.m.

Panel version: 3.1510

Caroline Wright (Sanger)

I don't know

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
OROFACIODIGITAL SYNDROME XIV

Publications

24997988

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

Lu Raymond (university of cambridge )

I don't know

Created: 23 Feb 2016, 10:02 a.m.

Panel version: 0.306

Richard Scott (Genomics England Curator)

Comment on list classification: 2 families reported to date - awaiting confirmation
Created: 3 Feb 2016, 12:09 p.m.

Created: 3 Feb 2016, 12:09 p.m.

Panel version: 0.57

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green
Victorian Clinical Genetics Services

Phenotypes

Orofaciodigital syndrome XIV, 615948
Joubert-related disorder

OMIM

615944

Clinvar variants

Variants in C2CD3

Penetrance

Complete

Publications

Panels with this gene