Submissions for variant NM_025114.4(CEP290):c.164_167del (p.Thr55fs)

dbSNP: rs758550675

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201609	SCV000256372	pathogenic	Joubert syndrome 5	2015-02-23	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243311	SCV001416459	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr55Serfs*3) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). This variant is present in population databases (rs758550675, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 17617513, 26092869). ClinVar contains an entry for this variant (Variation ID: 217624). 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.
Genome-Nilou Lab	RCV000201609	SCV001810325	pathogenic	Joubert syndrome 5	2021-07-22	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002466465	SCV002761489	pathogenic	Bardet-Biedl syndrome 14	2022-03-30	criteria provided, single submitter	clinical testing	The CEP290 c.164_167del variant is classified as a PATHOGENIC variant (PVS1, PM2, PS4_supporting) The variant is a 4-base pair deletion in exon 3/54 of the CEP290 gene which results in a frameshift starting at codon Threonine 55, changes this amino acid to an Serine, and creating a premature STOP codon 3 amino acids downstream (denoted p.Thr55Serfs*3) (PVS1). The variant has been reported in dbSNP (rs758550675) but is rare in the disease databases (gnomAD: 3/152112, 0 homozygote) (PM2). The variant has been reported in both ClinVar (ID: #217624) and HGMD (accession: CD075347) as a disease causing variant (PS4_supporting).
Fulgent Genetics, Fulgent Genetics	RCV002500630	SCV002809292	pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2021-10-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517310	SCV003630574	pathogenic	Inborn genetic diseases	2022-07-05	criteria provided, single submitter	clinical testing	The c.164_167delCTCA (p.T55Sfs*3) alteration, located in exon 3 (coding exon 2) of the CEP290 gene, consists of a deletion of 4 nucleotides from position 164 to 167, causing a translational frameshift with a predicted alternate stop codon after 3 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in conjunction with other pathogenic CEP290 mutations in multiple individuals with CEP290-related ciliopathies, including Leber congenital amaurosis (Bachmann-Gagescu, 2015; Schueler, 2016; Yohe, 2020; Sallum, 2020). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV002466465	SCV004216517	pathogenic	Bardet-Biedl syndrome 14	2024-03-26	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001833166	SCV004847464	pathogenic	Leber congenital amaurosis	2024-03-20	criteria provided, single submitter	clinical testing	The p.Thr55SerfsX3 variant in CEP290 has been reported in the compound heterozygous state in at least 7 individuals with CEP290-associated disorders (Bachmann-Gagescu 2015 PMID: 26092869, Schueler 2016 PMID: 26673778, Yohe 2020 PMID: 31816670, Sallum 2020 PMID: 32865313, Areblom 2023 PMID: 37510321, Li 2023 PMID: 36729443, Wang 2023 PMID: 36990420). It at least 5 individuals, this variant was reported with another disease-causing variant in CEP290, and the variants have been confirmed in trans in at least one individual. This variant segregated with disease in 1 affected relative from 1 family (Sallum 2020 PMID: 32865313). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 217624) and has been identified in 0.01% (1/5956) of Middle Eastern and 0.004% (3/74020) African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). This is consistent with the prevalence of the disease in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 55 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the CEP290 gene is an established disease mechanism in autosomal recessive CEP290-related ciliopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CEP290-related ciliopathy. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting, PP1.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV004765322	SCV005375323	pathogenic	Meckel syndrome, type 4	2024-09-10	criteria provided, single submitter	clinical testing	The p.Thr55Serfs*3 variant in CEP290 was seen in compound heterozygosity with a likely benign variant (p.Arg360Gln) in a fetus with complex ciliopathy with multiple malformations, polydactyly (preaxial in the hands, postaxial in the feet), microcephaly, molar tooth sign. The fetus was also heterozygous for a premature translational stop signal (p.Arg973*) in the CEP120 gene in the last exon.
Natera, Inc.	RCV001833166	SCV002094946	pathogenic	Leber congenital amaurosis	2020-10-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732781	SCV005360684	pathogenic	CEP290-related disorder	2024-04-17	no assertion criteria provided	clinical testing	The CEP290 c.164_167delCTCA variant is predicted to result in a frameshift and premature protein termination (p.Thr55Serfs*3). This variant was reported in patients with Joubert syndrome, Senior-Loken type (Helou et al 2007. PubMed ID: 17617513; Bachmann-Gagescu et al 2015. PubMed ID: 26092869). This variant is reported in 0.0071% of alleles in individuals of African descent in gnomAD. Loss-of-function variants in CEP290 have been documented to be disease causing (Sayer et al. 2006. PubMed ID: 16682973). This variant is interpreted as pathogenic.