Submissions for variant NM_001378615.1(CC2D2A):c.3850C>T (p.Arg1284Cys)

gnomAD frequency: 0.00002  dbSNP: rs779823379

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201552	SCV000256337	pathogenic	Joubert syndrome 9	2015-02-23	criteria provided, single submitter	research
Pathology and Clinical Laboratory Medicine, King Fahad Medical City	RCV001261604	SCV001438887	likely pathogenic	Meckel syndrome, type 6		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853232	SCV002271869	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1284 of the CC2D2A protein (p.Arg1284Cys). This variant is present in population databases (rs779823379, gnomAD 0.002%). This missense change has been observed in individual(s) with Joubert syndrome and related disorders (PMID: 22241855, 26092869, 27894351, 34645488). ClinVar contains an entry for this variant (Variation ID: 217597). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CC2D2A protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg1284 amino acid residue in CC2D2A. Other variant(s) that disrupt this residue have been observed in individuals with CC2D2A-related conditions (PMID: 22241855), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000201552	SCV004804891	pathogenic	Joubert syndrome 9	2024-03-17	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV005031761	SCV005664566	likely pathogenic	Meckel syndrome, type 6; Joubert syndrome 9; COACH syndrome 2; Retinitis pigmentosa 93	2024-04-12	criteria provided, single submitter	clinical testing