ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.4555A>T (p.Ile1519Leu)

gnomAD frequency: 0.00016  dbSNP: rs200817579
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232101 SCV000290913 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis 2022-09-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1519 of the CEP290 protein (p.Ile1519Leu). This variant is present in population databases (rs200817579, gnomAD 0.03%). 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: 241584). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CEP290 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina RCV000336910 SCV000381432 uncertain significance Bardet-Biedl syndrome 14 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000392673 SCV000381433 uncertain significance Joubert syndrome 5 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000311320 SCV000381434 uncertain significance Meckel syndrome, type 4 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000370677 SCV000381435 uncertain significance Senior-Loken syndrome 6 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000277527 SCV000381436 uncertain significance Leber congenital amaurosis 10 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome-Nilou Lab RCV000336910 SCV001781292 uncertain significance Bardet-Biedl syndrome 14 2021-07-14 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000392673 SCV001781293 uncertain significance Joubert syndrome 5 2021-07-14 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000311320 SCV001781294 uncertain significance Meckel syndrome, type 4 2021-07-14 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000370677 SCV001781295 uncertain significance Senior-Loken syndrome 6 2021-07-14 criteria provided, single submitter clinical testing
GeneDx RCV001699086 SCV001987439 uncertain significance not provided 2021-10-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV003278715 SCV004002704 uncertain significance Inborn genetic diseases 2023-03-20 criteria provided, single submitter clinical testing The c.4555A>T (p.I1519L) alteration is located in exon 35 (coding exon 34) of the CEP290 gene. This alteration results from a A to T substitution at nucleotide position 4555, causing the isoleucine (I) at amino acid position 1519 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Preventiongenetics, part of Exact Sciences RCV003401185 SCV004103121 uncertain significance CEP290-related condition 2023-10-12 criteria provided, single submitter clinical testing The CEP290 c.4555A>T variant is predicted to result in the amino acid substitution p.Ile1519Leu. This variant was reported in two siblings with Joubert syndrome; however, they both harbored two causative variants in CC2D2A which provided the diagnosis (Table S5, Phelps et al. 2018. PubMed ID: 28771248). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-88478512-T-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc. RCV001271570 SCV001452835 uncertain significance Leber congenital amaurosis 2020-09-16 no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV001699086 SCV001918484 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001701882 SCV001928905 benign not specified no assertion criteria provided clinical testing

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