Submissions for variant NM_025114.4(CEP290):c.4088G>A (p.Arg1363Gln)

gnomAD frequency: 0.00011  dbSNP: rs188502327

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067829	SCV001232910	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1363 of the CEP290 protein (p.Arg1363Gln). This variant is present in population databases (rs188502327, gnomAD 0.03%). 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: 861323). 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 create or strengthen a 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.
Illumina Laboratory Services, Illumina	RCV001114604	SCV001272504	uncertain significance	Meckel syndrome, type 4	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001114605	SCV001272505	uncertain significance	Joubert syndrome 5	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001114606	SCV001272506	uncertain significance	Senior-Loken syndrome 6	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001114607	SCV001272507	uncertain significance	Leber congenital amaurosis 10	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001114608	SCV001272508	uncertain significance	Bardet-Biedl syndrome 14	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001568234	SCV001792074	uncertain significance	not provided	2024-01-19	criteria provided, single submitter	clinical testing	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: 33616283, 37810530)
Natera, Inc.	RCV001833655	SCV002094237	uncertain significance	Leber congenital amaurosis	2020-01-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528370	SCV004112225	uncertain significance	CEP290-related disorder	2024-08-07	no assertion criteria provided	clinical testing	The CEP290 c.4088G>A variant is predicted to result in the amino acid substitution p.Arg1363Gln. This variant has been reported as an additional variant of uncertain significance in a retinitis pigmentosa patient who was positive in the USH2A gene (Wang et al. 2014. PubMed ID: 25097241, Table S3, Patient 30). It has also been reported in an individual with severe obesity (Day et al. 2021. PubMed ID: 33616283). This variant is reported in 0.035% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.