Submissions for variant NM_025114.4(CEP290):c.2615C>T (p.Ser872Leu)

gnomAD frequency: 0.00023  dbSNP: rs373341530

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001244964	SCV001418221	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 872 of the CEP290 protein (p.Ser872Leu). This variant is present in population databases (rs373341530, gnomAD 0.1%). 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: 969581). 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 not 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.
GeneDx	RCV001577091	SCV001804416	uncertain significance	not provided	2019-10-14	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002480831	SCV002781932	uncertain significance	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2022-03-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003426013	SCV004117186	uncertain significance	CEP290-related condition	2024-01-31	criteria provided, single submitter	clinical testing	The CEP290 c.2615C>T variant is predicted to result in the amino acid substitution p.Ser872Leu. The c.2615C>T variant was reported in the heterozygous state in one patient with retinitis pigmentosa; however, a second plausible causative variant was not identified in this patient’s CEP290 gene (Wang et al. 2014. 25097241). The p.Ser872Leu variant was also reported along with a second uncertain CEP290 variant in two siblings who presented with obesity; however both variants were found to be paternally inherited (Niazi et al. 2019. PubMed ID: 31488071). This variant is reported in 0.10% of alleles in individuals of South Asian descent in gnomAD. 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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252438	SCV001428194	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001577091	SCV002035699	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001577091	SCV002037672	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001835220	SCV002094282	uncertain significance	Leber congenital amaurosis	2020-01-22	no assertion criteria provided	clinical testing