ClinVar Miner

Submissions for variant NM_001378615.1(CC2D2A):c.4552C>T (p.Arg1518Trp)

dbSNP: rs767260373
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000703032 SCV000831912 pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1518 of the CC2D2A protein (p.Arg1518Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Joubert syndrome (PMID: 23692786; Invitae). ClinVar contains an entry for this variant (Variation ID: 579685). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CC2D2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000984486 SCV001132534 uncertain significance Joubert syndrome 9 2018-11-15 criteria provided, single submitter research The homozygous p.Arg1518Trp variant in CC2D2A was identified by our study in one individual with Joubert Syndrome. This variant has been identified in <0.01% (1/110440) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs767260373). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg1518Trp variant is uncertain.

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