Submissions for variant NM_025114.4(CEP290):c.4437+1G>A (rs760915898)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000498064	SCV000339179	pathogenic	not provided	2016-02-05	criteria provided, single submitter	clinical testing
Invitae	RCV000473837	SCV000541577	likely pathogenic	Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis	2019-12-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 34 of the CEP290 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs760915898, ExAC 0.005%). This variant has not been reported in the literature in individuals with CEP290-related disease. ClinVar contains an entry for this variant (Variation ID: 285948). Donor and acceptor splice site variants 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). 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.
GeneDx	RCV000498064	SCV000589312	likely pathogenic	not provided	2017-06-07	criteria provided, single submitter	clinical testing	The c.4437+1G>A variant in the CEP290 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 34. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.4437+1G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.4437+1G>A as a likely pathogenic variant.
Fulgent Genetics,Fulgent Genetics	RCV000763313	SCV000893990	likely 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
Illumina Clinical Services Laboratory,Illumina	RCV000779117	SCV000915611	uncertain significance	CEP290-Related Disorders	2018-12-06	criteria provided, single submitter	clinical testing	The CEP290 c.4437+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill	RCV000779117	SCV001251488	likely pathogenic	CEP290-Related Disorders		criteria provided, single submitter	research	The CEP290 c.4437+1G>A (p.?) variant is predicted to disrupt a canonical splice donor site, which may result in an aberrant protein. This variant has not been reported in association with CEP290-related disorders.