Submissions for variant NM_001378615.1(CC2D2A):c.2993AAG[2] (p.Glu1000del)

dbSNP: rs764874938

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000585193	SCV000693148	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000585193	SCV000704782	uncertain significance	not provided	2016-12-20	criteria provided, single submitter	clinical testing
Invitae	RCV001313276	SCV001503763	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This variant, c.2999_3001del, results in the deletion of 1 amino acid(s) of the CC2D2A protein (p.Glu1000del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs764874938, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CC2D2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 493392). This variant disrupts a region of the CC2D2A protein in which other variant(s) (p.Glu1000Val) have been determined to be pathogenic (PMID: 26092869, 26310553). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV001809687	SCV002058421	uncertain significance	Joubert syndrome 9	2022-01-03	criteria provided, single submitter	clinical testing	This inframe deletion in the non-repeat region can change the length of the protein and disrupt protein function (PM4_M). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000041, PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001809687	SCV002507063	uncertain significance	Joubert syndrome 9	2022-05-04	criteria provided, single submitter	curation	The homozygous p.Glu1000del variant in CC2D2A was identified by our study in 1 individual with Joubert syndrome 9. The variant has not been previously reported in individuals with Joubert syndrome 9 but has been identified in 0.007% (8/116028) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs764874938). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 493392) as having uncertain significance by EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, and CeGaT Praxis fuer Humangenetik Tuebingen. This variant is a deletion of 3 bases at position 2999 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM4_supporting, PM3_supporting (Richards 2015).
MGZ Medical Genetics Center	RCV001809687	SCV002579588	uncertain significance	Joubert syndrome 9	2021-11-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002497231	SCV002816789	uncertain significance	Meckel syndrome, type 6; Joubert syndrome 9; COACH syndrome 2; Retinitis pigmentosa 93	2021-09-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002530858	SCV003732130	uncertain significance	Inborn genetic diseases	2021-04-14	criteria provided, single submitter	clinical testing	The c.2999_3001delAAG (p.E1000del) alteration is located in exon 24 (coding exon 22) of the CC2D2A gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions c.2999 and c.3001, resulting in the deletion of 1 residue. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.