Submissions for variant NM_025114.4(CEP290):c.6645+1G>A

gnomAD frequency: 0.00006  dbSNP: rs201218801

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000454208	SCV000538016	likely pathogenic	Joubert syndrome 5	2016-03-30	criteria provided, single submitter	clinical testing	This c.6645+1G>A variant is predicted to affect the splice-donor site in intron 48 of the CEP290 gene. The frequency of this variant is very low in the ExAC database and is absent in both the 1000 Genomes and Exome Sequencing Project databases. In addition, splice-site computational algorithms have predicted this variant to abrogate splicing. Loss-of-function mutations are a known mechanism of disease for this disorder; therefore, we have provisionally classified this variant as Likely Pathogenic. We have confirmed this sequence change in our laboratory using Sanger sequencing. However, splicing studies are necessary to confirm this interpretation.
GeneDx	RCV000497486	SCV000590762	uncertain significance	not provided	2022-04-19	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29754767)
Eurofins Ntd Llc (ga)	RCV000497486	SCV000701396	likely pathogenic	not provided	2016-09-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801486	SCV000941263	likely pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 48 of the CEP290 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). This variant is present in population databases (rs201218801, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. ClinVar contains an entry for this variant (Variation ID: 290046). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Baylor Genetics	RCV001331377	SCV001523408	likely pathogenic	Meckel syndrome, type 4	2019-09-06	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Center for Human Genetics Tuebingen	RCV000497486	SCV001961366	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Suma Genomics	RCV001833396	SCV002097003	pathogenic	Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14		criteria provided, single submitter	clinical testing
New York Genome Center	RCV002467720	SCV002764443	likely pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5	2020-11-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002522012	SCV003695995	uncertain significance	Inborn genetic diseases	2021-09-21	criteria provided, single submitter	clinical testing	Punj, 2018_x000D_ _x000D_ Resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003463776	SCV004214821	likely pathogenic	Bardet-Biedl syndrome 14	2024-03-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537606	SCV004116654	likely pathogenic	CEP290-related disorder	2024-03-23	no assertion criteria provided	clinical testing	The CEP290 c.6645+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature in association with CEP290-related disease. This variant is reported in 0.019% of alleles in individuals of Latino descent in gnomAD. Splicing variants in CEP290 have been reported in patients with Joubert Syndrome, Meckel Syndrome, and Leber Congenital Amaurosis and are expected to be pathogenic (Baala et al. 2007. PubMed ID: 17564974; Perrault et al. 2007. PubMed ID: 17345604; Tory et al. 2007. PubMed ID: 17409309). This variant is interpreted as likely pathogenic.