ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.2991+1655A>G (rs281865192)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000086286 SCV000329242 pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing The c.2991+1655 A>G variant is the most common LCA pathogenic variant in North America and North Western Europe, as it was identified in 16 out of 76 unrelated LCA1 patients (21%) (den Hollander et al., 2006), and has been observed in the homozygous state in many affected patients (Yzer et al., 2012). The variant is observed in 3/14960 (0.0201%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). Functional studies have shown that c.2991+1655 A>G results in the insertion of an aberrant exon into approximately half of CEP290 transcripts, and reduces CEP290 mRNA levels in comparison to wild type (Garanto et al., 2015; Gerard et al., 2012). Therefore, we consider this variant to be pathogenic.
Invitae RCV000558460 SCV000634646 pathogenic Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2019-12-23 criteria provided, single submitter clinical testing This sequence change falls in intron 26 of the CEP290 gene. It does not directly change the encoded amino acid sequence of the CEP290 protein. This variant is the most commonly reported CEP290 variant in individuals of European descent who are affected with Leber congenital amaurosis (PMID: 16909394, 17345604, 17964524). It is also known as IVS26+1655A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 1337). Experimental studies have shown that this variant creates a cryptic splice site in intron 26, resulting in the insertion of 128bp of intronic sequence between exons 26 and 27 (PMID: 16909394). This "pseudoexon" contains a stop codon, and results in decreased CEP20 protein expression. It has also been shown that if the pseudoexon is induced to be skipped, using antisense oligonucleotides, protein expression and cilia formation can be restored in cultured cells (PMID: 23344081). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000086286 SCV000700700 pathogenic not provided 2017-07-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763315 SCV000893992 pathogenic Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000988884 SCV001138782 pathogenic Joubert syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075828 SCV001241465 pathogenic Retinal dystrophy 2019-07-25 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000086286 SCV001246570 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001195984 SCV001366411 pathogenic Ichthyosis (disease) 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM3,PP3,PP4. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001195986 SCV001366413 pathogenic Nystagmus; Abnormality of eye movement 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP4. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196010 SCV001366439 likely pathogenic Retinopathy 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3,PP4. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198979 SCV001369974 pathogenic Retinal dystrophy; Abnormality of vision 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. This variant was detected in heterozygous state.
Institute of Human Genetics, University of Leipzig Medical Center RCV001255341 SCV001431671 pathogenic Intellectual disability 2020-08-03 criteria provided, single submitter clinical testing The variant c.2991+1655A>G, was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was not maternal.The variant likely explains the NDD in this individual.
OMIM RCV000001400 SCV000021550 pathogenic Leber congenital amaurosis 10 2007-07-01 no assertion criteria provided literature only
GeneReviews RCV000001400 SCV000058614 pathologic Leber congenital amaurosis 10 2012-03-29 no assertion criteria provided curation Converted during submission to Pathogenic.
GeneReviews RCV000001400 SCV000087012 pathologic Leber congenital amaurosis 10 2013-05-02 no assertion criteria provided curation Converted during submission to Pathogenic.
Retina International RCV000086286 SCV000118432 not provided not provided no assertion provided not provided
Human Genetics - Radboudumc,Radboudumc RCV000678535 SCV000804609 pathogenic Retinitis pigmentosa 2016-09-01 no assertion criteria provided clinical testing

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