Submissions for variant NM_025114.4(CEP290):c.1670G>A (p.Arg557His)

gnomAD frequency: 0.00064  dbSNP: rs184018899

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485164	SCV000564859	uncertain significance	not specified	2016-04-04	criteria provided, single submitter	clinical testing	The R557H variant in the CEP290 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R557H variant was not observed at any significant frequency in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R557H variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R557H as a variant of uncertain significance.
Invitae	RCV000554377	SCV000634640	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 557 of the CEP290 protein (p.Arg557His). This variant is present in population databases (rs184018899, gnomAD 0.07%). 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: 418122). 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.
Eurofins Ntd Llc (ga)	RCV000723705	SCV000700623	uncertain significance	not provided	2017-05-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763867	SCV000894801	uncertain significance	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
CeGaT Center for Human Genetics Tuebingen	RCV000723705	SCV001148793	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing	CEP290: PM2, BP4
Illumina Laboratory Services, Illumina	RCV001111900	SCV001269507	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	RCV001111901	SCV001269508	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	RCV001111902	SCV001269509	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	RCV001111903	SCV001269510	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	RCV001111904	SCV001269511	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.
New York Genome Center	RCV003227766	SCV003925096	uncertain significance	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5	2022-04-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529604	SCV004111938	uncertain significance	CEP290-related disorder	2024-02-13	criteria provided, single submitter	clinical testing	The CEP290 c.1670G>A variant is predicted to result in the amino acid substitution p.Arg557His. This variant is documented in the heterozygous state in a patient with retinitis pigmentosa; however, no additional functional or family segregation studies tested its pathogenicity (McGowan et al. 2020. PubMed ID: 32579692). Additionally, this variant was described in the heterozygous state in an individual who already carried a known pathogenic variant in CRYAB (Marcos et al. 2020. PubMed ID: 32420686). However, this variant is reported in 0.075% of alleles in individuals of European (non-Finnish) descent in gnomAD, which may be too frequent to be a primary cause of disease. Although we suspect that this variant may be benign, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence.
Revvity Omics, Revvity	RCV000723705	SCV004235028	uncertain significance	not provided	2023-04-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001275035	SCV001459789	uncertain significance	Leber congenital amaurosis	2020-04-17	no assertion criteria provided	clinical testing