ClinVar Miner

Submissions for variant NM_025114.3(CEP290):c.2991+1655A>G (rs281865192)

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Total submissions: 9
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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 2018-11-19 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
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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