Submissions for variant NM_025114.4(CEP290):c.3175dup (p.Ile1059fs)

dbSNP: rs62640570

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000114193	SCV000147746	pathogenic	Meckel-Gruber syndrome	2013-08-02	criteria provided, single submitter	clinical testing
UW Hindbrain Malformation Research Program, University of Washington	RCV000201666	SCV000256384	pathogenic	Joubert syndrome 5	2015-02-23	criteria provided, single submitter	research
GeneDx	RCV000086287	SCV000589618	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing	Frameshift 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; Reported multiple times previously in association with CEP290-related disorders (Sayer et al., 2006; Chaki et al., 2011; Yzer et al., 2012); This variant is associated with the following publications: (PMID: 23559409, 16682973, 24946806, 19466712, 22355252, 21866095, 17564974, 29398085)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695282	SCV000823771	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile1059Asnfs*11) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Joubert syndrome and/or Leber congenital amaurosis (PMID: 16682973, 17345604, 21245082, 22355252, 25920555). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.3175-3176insA and c.3175insA. ClinVar contains an entry for this variant (Variation ID: 99850). 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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000201666	SCV001149704	pathogenic	Joubert syndrome 5	2020-01-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000086287	SCV001246569	pathogenic	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003315227	SCV004014861	pathogenic	CEP290-related disorder		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 28 of 54 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in CEP290 is an established mechanism of disease (PMID: 32600475, 20301500, 16909394, 20690115). This variant has been previously reported as a compound heterozygous change in patients with Leber congenital amaurosis and Meckel syndrome (PMID: 22355252, 16682973,29398085, 35352487, 29178642). The c.3175dup (p.Ile1059AsnFsTer11) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (16/271936), and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, c.3175dup (p.Ile1059AsnFsTer11) is classified as Pathogenic.
Baylor Genetics	RCV003460787	SCV004214823	pathogenic	Bardet-Biedl syndrome 14	2024-03-27	criteria provided, single submitter	clinical testing
Retina International	RCV000086287	SCV000118433	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV001271580	SCV001452847	pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000086287	SCV001740661	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000086287	SCV001808681	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000086287	SCV001918757	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000086287	SCV001928768	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000086287	SCV001954399	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000086287	SCV001975361	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003315227	SCV005353627	pathogenic	CEP290-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The CEP290 c.3175dupA variant is predicted to result in a frameshift and premature protein termination (p.Ile1059Asnfs*11). This variant has previously been reported to be causative for Joubert syndrome (Sayer et al. 2006. PubMed ID: 16682973; Chaki et al. 2011. PubMed ID: 21866095) and Leber congenital amaurosis (LCA) (Yzer et al. 2012. PubMed ID: 22355252). This variant is reported in 0.0096% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic.