Submissions for variant NM_025114.4(CEP290):c.6628C>T (p.Arg2210Cys)

gnomAD frequency: 0.00024  dbSNP: rs374852145

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483414	SCV000568654	uncertain significance	not provided	2024-01-25	criteria provided, single submitter	clinical testing	Observed as a heterozygous variant in a fetus with posterior encephalocele, abnormal posterior fossa, multicystic dysplastic kidneys, club feet, shortened limbs and ambiguous genitalia who also harbored a splice site variant in the B9D1 gene; a second CEP290 variant was not identified (PMID: 21493627); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21493627)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636992	SCV000758440	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2210 of the CEP290 protein (p.Arg2210Cys). This variant is present in population databases (rs374852145, gnomAD 0.04%). This missense change has been observed in individual(s) with Meckel syndrome (PMID: 21493627). ClinVar contains an entry for this variant (Variation ID: 420090). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000483414	SCV001148787	uncertain significance	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV002056756	SCV002496402	uncertain significance	Bardet-Biedl syndrome 14	2022-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481511	SCV002791866	uncertain significance	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2022-04-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509404	SCV002819725	uncertain significance	not specified	2022-12-21	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.6628C>T (p.Arg2210Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 221622 control chromosomes (gnomAD). c.6628C>T has been reported in the literature in at least one individual affected with Meckel syndrome, however, this individual also had compound heterozygous pathogenic variants in B9D1 (Hopp_2011). This report does not provide unequivocal conclusions about association of the variant with CEP290-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) have cited the variant, with all laboratories classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000483414	SCV003831589	uncertain significance	not provided	2020-10-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001833611	SCV002091833	uncertain significance	Leber congenital amaurosis	2020-01-22	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535509	SCV004114748	uncertain significance	CEP290-related disorder	2024-06-05	no assertion criteria provided	clinical testing	The CEP290 c.6628C>T variant is predicted to result in the amino acid substitution p.Arg2210Cys. This variant has been reported in a heterozygous state in a fetus with Meckel syndrome; however, the fetus was compound heterozygous for loss of function variants in ciliopathy gene B9D1 (Family M456, Hopp et al. 2011. PubMed ID: 21493627). This variant is reported in 0.042% 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.