Submissions for variant NM_025114.4(CEP290):c.4682G>A (p.Arg1561His)

dbSNP: rs371157150

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001652983	SCV001871041	uncertain significance	not provided	2021-08-11	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002266008	SCV002547589	uncertain significance	not specified	2022-05-17	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.4682G>A (p.Arg1561His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 248656 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CEP290 causing Meckel Syndrome Type 4 (4.8e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4682G>A in individuals affected with Meckel Syndrome Type 4 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002539602	SCV003272904	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1561 of the CEP290 protein (p.Arg1561His). This variant is present in population databases (rs371157150, gnomAD 0.01%). 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: 1254201). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Natera, Inc.	RCV001827558	SCV002094212	uncertain significance	Leber congenital amaurosis	2020-02-13	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528526	SCV004107153	uncertain significance	CEP290-related disorder	2024-01-23	no assertion criteria provided	clinical testing	The CEP290 c.4682G>A variant is predicted to result in the amino acid substitution p.Arg1561His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.