Submissions for variant NM_025114.4(CEP290):c.7015C>T (p.Arg2339Trp)

gnomAD frequency: 0.00019  dbSNP: rs200969981

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243915	SCV001417104	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2339 of the CEP290 protein (p.Arg2339Trp). This variant is present in population databases (rs200969981, 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: 968717). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx	RCV001354642	SCV002030976	uncertain significance	not provided	2024-10-24	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in a patient with Bardet-Biedl syndrome in published literature (PMID: 39092430); In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 39092430)
Fulgent Genetics, Fulgent Genetics	RCV002480820	SCV002786108	uncertain significance	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2021-12-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001354642	SCV004135534	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	CEP290: BP4
DNA-diagnostics Laboratory, Research Centre For Medical Genetics	RCV004577955	SCV005061803	likely pathogenic	Bardet-Biedl syndrome 14		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004609704	SCV005105321	uncertain significance	Inborn genetic diseases	2024-06-22	criteria provided, single submitter	clinical testing	The c.7015C>T (p.R2339W) alteration is located in exon 51 (coding exon 50) of the CEP290 gene. This alteration results from a C to T substitution at nucleotide position 7015, causing the arginine (R) at amino acid position 2339 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354642	SCV001549306	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CEP290 p.R2339W variant was not identified in the literature but was identified in dbSNP (ID: rs200969981) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 46 of 276868 chromosomes at a frequency of 0.0001661 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.R2339 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV001835188	SCV002091821	uncertain significance	Leber congenital amaurosis	2020-02-13	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538510	SCV004104167	uncertain significance	CEP290-related disorder	2024-06-28	no assertion criteria provided	clinical testing	The CEP290 c.7015C>T variant is predicted to result in the amino acid substitution p.Arg2339Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.