Submissions for variant NM_001378615.1(CC2D2A):c.3774dup (p.Glu1259Ter)

dbSNP: rs386833757

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201709	SCV000256353	pathogenic	Joubert syndrome 9	2015-02-23	criteria provided, single submitter	research
GeneDx	RCV000373656	SCV000329214	pathogenic	not provided	2022-01-12	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24706459, 26729329, 21866095, 26092869, 21068128, 33486889)
Eurofins Ntd Llc (ga)	RCV000373656	SCV000703056	pathogenic	not provided	2016-10-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389255	SCV001590546	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1259*) in the CC2D2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CC2D2A are known to be pathogenic (PMID: 19777577). This variant is present in population databases (rs757195653, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with CC2D2A-related conditions (PMID: 21068128, 26092869). ClinVar contains an entry for this variant (Variation ID: 56309). 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.
Genomics England Pilot Project, Genomics England	RCV001542749	SCV001760132	pathogenic	COACH syndrome 1		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000373656	SCV002016951	pathogenic	not provided	2022-12-21	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993780	SCV004812674	pathogenic	Ciliopathy	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change in CC2D2A is a frameshift variant predicted to cause a premature stop codon, p.(Glu1259*), in biologically relevant exon 30/37 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.03% (314/1,178,816 alleles) in the European (non-Finnish) population, consistent with a recessive disease. This variant has been detected in at least five individuals with a phenotype consistent with a ciliopathy (Meckel syndrome and Joubert syndrome) in the compound heterozygous state (with at least one individual with a pathogenic variant on the other allele; PMID: 21068128, 24706459, 26092869, 26729329). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PM2_Supporting.
Fulgent Genetics, Fulgent Genetics	RCV005031534	SCV005664563	pathogenic	Meckel syndrome, type 6; Joubert syndrome 9; COACH syndrome 2; Retinitis pigmentosa 93	2024-03-21	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049721	SCV000082128	probable-pathogenic	Meckel syndrome, type 6		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004732639	SCV005361148	pathogenic	CC2D2A-related disorder	2024-03-16	no assertion criteria provided	clinical testing	The CC2D2A c.3774dupT variant is predicted to result in premature protein termination (p.Glu1259*). This variant has been reported in individuals with Meckel-Gruber syndrome (Otto et al. 2011. PubMed ID: 21068128; Jones et al. 2014. PubMed ID: 24706459). This variant is reported in 0.012% of alleles in individuals of European (non-Finnish) descent in gnomAD. Truncating variants in CC2D2A are expected to be pathogenic. This variant is interpreted as pathogenic.