Submissions for variant NM_025114.4(CEP290):c.4805C>T (p.Thr1602Met)

gnomAD frequency: 0.00006  dbSNP: rs369451049

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001000093	SCV000930044	likely pathogenic	Meckel syndrome, type 4		criteria provided, single submitter	research
Invitae	RCV001244303	SCV001417512	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1602 of the CEP290 protein (p.Thr1602Met). This variant is present in population databases (rs369451049, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of CEP290-related conditions (PMID: 31411728). ClinVar contains an entry for this variant (Variation ID: 684612). 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.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003448352	SCV004176361	uncertain significance	Bardet-Biedl syndrome 14	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.4805C>T (p.Thr1602Met) variant in the CEP290 gene has been observed in individual(s) with clinical features of CEP290-related conditions (Radhakrishnan, Periyasamy et al.,2019). This variant is reported with the allele frequency (0.02%) in the gnomAD Exomes and novel in 1000. It is submitted to ClinVar as Likely Pathogenic/ Uncertain Significance. The amino acid Threonine at position 1602 is changed to a Methionine changing protein sequence and it might alter its composition and physico- chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Thr1602Met in CEP290 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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. In the absence of another reportable variant, the molecular diagnosis is not confirmed.
Dept Of Ophthalmology, Nagoya University	RCV003889992	SCV004707659	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003938203	SCV004754865	uncertain significance	CEP290-related condition	2024-01-01	criteria provided, single submitter	clinical testing	The CEP290 c.4805C>T variant is predicted to result in the amino acid substitution p.Thr1602Met. This variant has been reported in the compound heterozygotes state in a patient with Meckel syndrome (Radhakrishnan et al. 2019. PubMed ID: 31411728). This variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV001830860	SCV002094208	uncertain significance	Leber congenital amaurosis	2020-01-24	no assertion criteria provided	clinical testing