ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.4754A>G (p.His1585Arg) (rs199826787)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000203104 SCV000258200 uncertain significance not specified 2015-02-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000379773 SCV000381427 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 Clinical Services Laboratory,Illumina RCV000285366 SCV000381428 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.
Illumina Clinical Services Laboratory,Illumina RCV000335594 SCV000381429 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 Clinical Services Laboratory,Illumina RCV000401171 SCV000381430 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 Clinical Services Laboratory,Illumina RCV000300690 SCV000381431 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.
Invitae RCV000815427 SCV000955879 uncertain significance Joubert syndrome; Meckel-Gruber syndrome; Nephronophthisis 2019-09-28 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1585 of the CEP290 protein (p.His1585Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs199826787, ExAC 0.03%). This variant has not been reported in the literature in individuals with CEP290-related disease. ClinVar contains an entry for this variant (Variation ID: 218802). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000203104 SCV001157854 uncertain significance not specified 2018-09-27 criteria provided, single submitter clinical testing The CEP290 c.4754A>G; p.His1585Arg variant (rs199826787), to our knowledge, is not reported in the medical literature or gene-specific databases. However, ARUP Laboratories has detected this variant in an individual with an alternative molecular explanation for disease. The variant is reported as a variant of uncertain significance in the ClinVar database (Variation ID: 218802) and in the general population with an overall allele frequency of 0.01% (35/257,682 alleles) in the Genome Aggregation Database. The histidine at this position is highly conserved but computational analyses (SIFT: Tolerated, PolyPhen-2:Probably Damaging) predict conflicting effects of this variant on protein structure/function. Considering available information, the clinical significance of this variant is uncertain. Pathogenic CEP290 variants are causative for autosomal recessive Leber Congenital Amaurosis (MIM: 611755), Joubert syndrome (MIM: 610188), Meckel syndrome (MIM: 611134), or Senior-Loken syndrome (MIM:610189).

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