Submissions for variant NM_025114.4(CEP290):c.1079G>A (p.Arg360Gln)

gnomAD frequency: 0.00405  dbSNP: rs188164241

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000152980	SCV000202421	likely benign	not specified	2015-02-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084283	SCV000253610	likely benign	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000152980	SCV000314512	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000152980	SCV000512568	likely benign	not specified	2017-11-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000658663	SCV000602964	likely benign	not provided	2023-09-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000658663	SCV000780446	benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	CEP290: BS1, BS2
Mendelics	RCV000988890	SCV001138788	likely benign	Joubert syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001110567	SCV001268017	uncertain significance	Bardet-Biedl syndrome 14	2018-01-13	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	RCV001110568	SCV001268018	uncertain significance	Meckel syndrome, type 4	2018-01-13	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	RCV001110569	SCV001268019	likely benign	Senior-Loken syndrome 6	2018-01-13	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001110570	SCV001268020	uncertain significance	Joubert syndrome 5	2018-01-13	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	RCV001110571	SCV001268021	uncertain significance	Leber congenital amaurosis 10	2018-01-13	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.
Genome-Nilou Lab	RCV001110567	SCV001781516	uncertain significance	Bardet-Biedl syndrome 14	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001110570	SCV001781517	uncertain significance	Joubert syndrome 5	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001110568	SCV001781518	uncertain significance	Meckel syndrome, type 4	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001110569	SCV001781519	uncertain significance	Senior-Loken syndrome 6	2021-07-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000152980	SCV002068810	likely benign	not specified	2019-08-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152980	SCV002500310	uncertain significance	not specified	2022-03-10	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.1079G>A (p.Arg360Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0039 in 150552 control chromosomes in the gnomAD database, including 4 homozygotes (gnomAD v3.1.2). c.1079G>A has been reported in the literature in two homozygous individuals affected with type 2 diabetes (Lim_2014) and in heterozygous individuals affected with Leber congenital amaurosis and left ventricular outflow defects (Haer-Wigman_2017, Watkins_2019). In addition, the variant has been reported in a cerebellar ataxia case along with another CEP290 pathogenic variant (Coutelier_2018) and in an individual affected with a rare disorder (exact phenotype not specified) in compound heterozygosity with a pathogenic variant (Stranneheim_2021). These reports do 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. Nine ClinVar submitters (evaluation after 2014) cite the variant as likely benign and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical and/or functional importance become available.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294046	SCV002587716	uncertain significance	Atypical hemolytic-uremic syndrome	2017-08-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000658663	SCV003831584	uncertain significance	not provided	2022-06-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001110568	SCV005375322	likely benign	Meckel syndrome, type 4	2024-09-10	criteria provided, single submitter	clinical testing	Common in public databases; MAF 1.4% i the European Finnish population and in total 10 homozygous individuals (gnomAD v4.1.0 non-UKB). The p.Arg360Gln variant in CEP290 was seen in a fetus with multiple malformations, preaxial polydactyly (feet) and postaxial polydactyly (hands), microcephaly, molar tooth sign. The variant is found in compound heterozygsity together with a likely pathogenic variant p.Thr55Serfs*3 in CEP290.
Natera, Inc.	RCV001275040	SCV001459794	likely benign	Leber congenital amaurosis	2020-04-17	no assertion criteria provided	clinical testing