Submissions for variant NM_025114.4(CEP290):c.3660G>T (p.Lys1220Asn)

gnomAD frequency: 0.00024  dbSNP: rs201982308

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724196	SCV000229464	uncertain significance	not provided	2017-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000724196	SCV000564861	uncertain significance	not provided	2021-12-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV000763865	SCV000894799	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
Invitae	RCV000797414	SCV000936969	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1220 of the CEP290 protein (p.Lys1220Asn). This variant is present in population databases (rs201982308, gnomAD 0.05%). 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: 196713). 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 expected to disrupt CEP290 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.
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV002054097	SCV002496403	uncertain significance	Bardet-Biedl syndrome 14	2022-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165371	SCV003865232	uncertain significance	Inborn genetic diseases	2023-02-28	criteria provided, single submitter	clinical testing	The c.3660G>T (p.K1220N) alteration is located in exon 31 (coding exon 30) of the CEP290 gene. This alteration results from a G to T substitution at nucleotide position 3660, causing the lysine (K) at amino acid position 1220 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003430728	SCV004116556	uncertain significance	CEP290-related condition	2023-12-20	criteria provided, single submitter	clinical testing	The CEP290 c.3660G>T variant is predicted to result in the amino acid substitution p.Lys1220Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.047% 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.
Natera, Inc.	RCV001832016	SCV002094254	uncertain significance	Leber congenital amaurosis	2020-02-21	no assertion criteria provided	clinical testing