Submissions for variant NM_025114.4(CEP290):c.6116A>G (p.Asp2039Gly)

gnomAD frequency: 0.00032  dbSNP: rs192259143

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725337	SCV000336125	uncertain significance	not provided	2015-10-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000307421	SCV000381331	uncertain significance	Leber congenital amaurosis 10	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000359847	SCV000381332	uncertain significance	Senior-Loken syndrome 6	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000267679	SCV000381333	uncertain significance	Bardet-Biedl syndrome 14	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000320391	SCV000381334	uncertain significance	Joubert syndrome 5	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000359078	SCV000381335	uncertain significance	Meckel syndrome, type 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000725337	SCV000725720	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing	Observed with another variant in CEP290 (phase unknown) in an individual with retinitis pigmentosa and as a heterozygous variant in an individual with retinopathy (Takahashi et al., 2019; Stanwyck et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31193260, 34426522, 31370859)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241619	SCV001414649	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2039 of the CEP290 protein (p.Asp2039Gly). This variant is present in population databases (rs192259143, 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: 283803). 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.
Genome-Nilou Lab	RCV000320391	SCV001653415	uncertain significance	Joubert syndrome 5	2021-05-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725337	SCV004700431	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	CEP290: PM2, PM3:Supporting, BP4
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252444	SCV001428200	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000725337	SCV001743734	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725337	SCV001975518	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001828196	SCV002091852	uncertain significance	Leber congenital amaurosis	2020-02-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529465	SCV004109805	uncertain significance	CEP290-related disorder	2024-04-26	no assertion criteria provided	clinical testing	The CEP290 c.6116A>G variant is predicted to result in the amino acid substitution p.Asp2039Gly. This variant was previously reported, along with a second variant in the same gene, in an individual who presented with suspected autosomal recessive retinitis pigmentosa (Takahashi et al. 2019. PubMed ID: 31370859). This variant was also reported in the heterozygous state in an individual who presented with suspected autoimmune retinopathy (Stanwyck et al. 2019. PubMed ID: 31193260). This variant is reported in 0.052% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.