Submissions for variant NM_025114.4(CEP290):c.2551G>A (p.Val851Ile)

gnomAD frequency: 0.00001  dbSNP: rs764963626

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228050	SCV000290912	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 851 of the CEP290 protein (p.Val851Ile). This variant is present in population databases (rs764963626, 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: 241583). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Fulgent Genetics, Fulgent Genetics	RCV000763866	SCV000894800	uncertain significance	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2022-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV002274949	SCV002562550	likely benign	not provided	2022-08-10	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Ambry Genetics	RCV002518359	SCV003724931	likely benign	Inborn genetic diseases	2021-06-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
New York Genome Center	RCV003227727	SCV003925134	uncertain significance	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5	2022-05-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001271583	SCV001452850	uncertain significance	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529413	SCV004108222	uncertain significance	CEP290-related disorder	2024-08-19	no assertion criteria provided	clinical testing	The CEP290 c.2551G>A variant is predicted to result in the amino acid substitution p.Val851Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.075% of alleles in individuals of Latino descent in gnomAD, which may be too frequent to be an unreported primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.