Submissions for variant NM_001378615.1(CC2D2A):c.2999A>T (p.Glu1000Val)

gnomAD frequency: 0.00001  dbSNP: rs773881370

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201775	SCV000256345	pathogenic	Joubert syndrome 9	2015-02-23	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853233	SCV002234371	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-05-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1000 of the CC2D2A protein (p.Glu1000Val). This variant is present in population databases (rs773881370, gnomAD 0.003%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26310553). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217604). 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 not expected to disrupt CC2D2A protein function with a negative 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. For these reasons, this variant has been classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796099	SCV005417902	pathogenic	Meckel syndrome, type 6; Joubert syndrome 9; COACH syndrome 2; Retinitis pigmentosa 93		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PP1
Fulgent Genetics, Fulgent Genetics	RCV004796099	SCV005662448	likely pathogenic	Meckel syndrome, type 6; Joubert syndrome 9; COACH syndrome 2; Retinitis pigmentosa 93	2024-03-19	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000201775	SCV001368618	uncertain significance	Joubert syndrome 9	2018-10-30	flagged submission	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP5.