Submissions for variant NM_001378615.1(CC2D2A):c.4553G>A (p.Arg1518Gln)

gnomAD frequency: 0.00005  dbSNP: rs200645738

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000728777	SCV000856391	uncertain significance	not provided	2017-08-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245116	SCV001418384	likely pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1518 of the CC2D2A protein (p.Arg1518Gln). This variant is present in population databases (rs200645738, gnomAD 0.09%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 25920555). ClinVar contains an entry for this variant (Variation ID: 593667). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CC2D2A protein function. This variant disrupts the p.Arg1518 amino acid residue in CC2D2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23692786). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV000728777	SCV001765941	uncertain significance	not provided	2020-08-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994099	SCV004813767	uncertain significance	not specified	2024-02-27	criteria provided, single submitter	clinical testing	Variant summary: CC2D2A c.4553G>A (p.Arg1518Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 246498 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CC2D2A causing Meckel Syndrome Type 6 (0.00015 vs 0.0011), allowing no conclusion about variant significance. c.4553G>A has been reported in the literature in at least one heterozygous individual affected with Joubert syndrome with no reported second variant in CC2D2A (e.g. Kroes_2016). This report does not provide unequivocal conclusions about association of the variant with Meckel Syndrome Type 6. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25920555). ClinVar contains an entry for this variant (Variation ID: 593667). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005036052	SCV005664609	uncertain significance	Meckel syndrome, type 6; Joubert syndrome 9; COACH syndrome 2; Retinitis pigmentosa 93	2024-06-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000728777	SCV001978412	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000728777	SCV001980269	uncertain significance	not provided		no assertion criteria provided	clinical testing