Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| UW Hindbrain Malformation Research Program, |
RCV000201720 | SCV000256333 | pathogenic | Joubert syndrome 9 | 2015-02-23 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV001234448 | SCV001407095 | uncertain significance | Familial aplasia of the vermis; Meckel-Gruber syndrome | 2019-08-25 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in combination with another CC2D2A variant in an individual affected with Joubert syndrome (PMID: 18950740). ClinVar contains an entry for this variant (Variation ID: 217595). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 1096 of the CC2D2A protein (p.Gln1096His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 26 of the CC2D2A coding sequence, which is part of the consensus splice site for this exon. |
| Molecular Genetics, |
RCV003993887 | SCV004812679 | likely pathogenic | Ciliopathy | 2024-03-01 | criteria provided, single submitter | clinical testing | This sequence change in CC2D2A is predicted to replace glutamine with histidine at codon 1096, p.(Gln1096His). The glutamine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the C2 domain. There is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 25 of the CC2D2A coding sequence, which is part of the consensus splice site for this exon. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.001% (13/1,110,402 alleles) in the European (non-Finnish) population, consistent with a recessive disease. This variant has been detected in at least two individuals (compound heterozygous with a pathogenic variant on the other allele) with a phenotype consistent with a ciliopathy (Joubert syndrome; PMID: 18950740, 38259611). Computational evidence predicts an impact on splicing (SpliceAI) for the nucleotide change and predicts a deleterious effect for the missense substitution (REVEL = 0.808). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2_Supporting, PM3_Strong, PP3. |