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

gnomAD frequency: 0.00006  dbSNP: rs199826787

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203104	SCV000258200	uncertain significance	not specified	2015-02-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1585 of the CEP290 protein (p.His1585Arg). This variant is present in population databases (rs199826787, gnomAD 0.04%). 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: 218802). 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 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.
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).
Genome-Nilou Lab	RCV000335594	SCV001781280	uncertain significance	Bardet-Biedl syndrome 14	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000300690	SCV001781281	uncertain significance	Joubert syndrome 5	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000379773	SCV001781282	uncertain significance	Meckel syndrome, type 4	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000401171	SCV001781283	uncertain significance	Senior-Loken syndrome 6	2021-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001582702	SCV001812939	uncertain significance	not provided	2023-06-16	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	RCV002515507	SCV003740943	uncertain significance	Inborn genetic diseases	2021-01-06	criteria provided, single submitter	clinical testing	The c.4754A>G (p.H1585R) alteration is located in exon 36 (coding exon 35) of the CEP290 gene. This alteration results from a A to G substitution at nucleotide position 4754, causing the histidine (H) at amino acid position 1585 to be replaced by an arginine (R). The in silico prediction for the p.H1585R alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003430760	SCV004118265	uncertain significance	CEP290-related condition	2024-01-29	criteria provided, single submitter	clinical testing	The CEP290 c.4754A>G variant is predicted to result in the amino acid substitution p.His1585Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.040% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV001273066	SCV001455653	uncertain significance	Leber congenital amaurosis	2020-01-24	no assertion criteria provided	clinical testing