Submissions for variant NM_025114.4(CEP290):c.4966G>T (p.Glu1656Ter)

gnomAD frequency: 0.00006  dbSNP: rs62638179

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000263885	SCV000381416	likely pathogenic	CEP290-related disorder	2017-04-28	criteria provided, single submitter	clinical testing	The CEP290 c.4966G>T (p.Glu1656Ter) variant is a stop-gained variant predicted to result in a premature truncation of the protein. The p.Glu1656Ter variant has been reported in three studies in patients with CEP290-related disorders in which it is found in a total of four affected individuals with Leber congenital amaurosis including three in a compound heterozygous state, all with the same known pathogenic stop-gained variant on the second allele, and one in a heterozygous state (den Hollander et al. 2006; Walia et al. 2010; Halbritter et al. 2013). This variant has not been reported in the literature in individuals with other CEP290-related phenotypes. The p.Glu1656Ter variant was absent from 192 controls and is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium though this is based on only two alleles in a region of good sequence coverage so the variant is presumed rare. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Glu1656Ter variant is classified as likely pathogenic for CEP290-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637002	SCV000758450	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1656*) 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 (rs62638179, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis, Joubert syndrome, or nephronophthisis-associated ciliopathy (PMID: 16909394, 20079931, 23188109, 23559409, 28497568). ClinVar contains an entry for this variant (Variation ID: 99857). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000086294	SCV000890285	pathogenic	not provided	2022-08-07	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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16909394, 25525159, 26529047, 28497568, 23559409, 26062849, 20079931, 19466712, 29398085, 23188109)
Baylor Genetics	RCV001335142	SCV001528206	pathogenic	Senior-Loken syndrome 6	2018-04-09	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple patients as disease causing [PMID 16909394, 28497568]
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723671	SCV001950229	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Glu1656Ter variant in CEP290 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002227445	SCV002507073	pathogenic	Leber congenital amaurosis 10	2022-05-04	criteria provided, single submitter	curation	The heterozygous p.Glu1656Ter variant in CEP290 was identified by our study in the compound heterozygous state, along with a variant of uncertain significance, in 1 individual with Leber congenital amaurosis 10. The variant has been reported in at least 2 individuals of unknown ethnicity with Leber congenital amaurosis 10 (PMID: 20079931), and has been identified in 0.0096% (7/72796) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs62638179). 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: 99857) as pathogenic by GeneDx and Invitae, and as likely pathogenic by Illumina Clinical Services Laboratory. This nonsense variant leads to a premature termination codon at position 1656, which is predicted to lead to a truncated or absent protein. Loss of function of the CEP290 gene is an established disease mechanism in autosomal recessive Leber congenital amaurosis 10. The presence of this variant in combination with reported pathogenic variants, and in at least 2 individuals with Leber congenital amaurosis 10 increases the likelihood that the p.Glu1656Ter variant is pathogenic (PMID: 20079931). In summary, this variant meets criteria to be classified as pathogenic for Leber congenital amaurosis 10 in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic CEP290 variants in affected individuals. ACMG/AMP Criteria applied: PVS1, PM2, PM3 (Richards 2015).
Baylor Genetics	RCV003467014	SCV004216546	pathogenic	Bardet-Biedl syndrome 14	2024-03-24	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004593991	SCV005086857	pathogenic	CEP290-related ciliopathy	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 5 (MIM#610188), Leber congenital amaurosis 10 (MIM#611755), Meckel syndrome 4 (MIM#611134), Senior-Loken syndrome 6 (MIM#610189). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (9 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by multiple clinical laboratories in ClinVar, and has been reported in individuals with CEP290-related conditions in the literature including three individuals with Leber congenital amaurosis where the variant was observed as compound heterozygous (PMID: 29398085). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Retina International	RCV000086294	SCV000118440	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV001276492	SCV001462871	pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000263885	SCV004114011	pathogenic	CEP290-related disorder	2024-01-22	no assertion criteria provided	clinical testing	The CEP290 c.4966G>T variant is predicted to result in premature protein termination (p.Glu1656*). This variant has been reported in the compound heterozygous state in individuals with Leber congenital amaurosis or Joubert syndrome (den Hollander et al. 2006. PubMed ID: 16909394; Table S2, Summers et al. 2017. PubMed ID: 28497568; Sheck et al. 2018. PubMed ID: 29398085; Walia et al. 2010. PubMed ID: 20079931). This variant is reported in 0.0096% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic.