Submissions for variant NM_025114.4(CEP290):c.4237G>C (p.Asp1413His)

gnomAD frequency: 0.00187  dbSNP: rs183655276

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082249	SCV000114198	likely benign	not specified	2015-03-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000082249	SCV000246994	uncertain significance	not specified	2014-05-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000351974	SCV000381452	likely benign	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 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	RCV000402012	SCV000381453	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.
Illumina Laboratory Services, Illumina	RCV000307654	SCV000381454	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	RCV000366483	SCV000381455	likely benign	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 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	RCV000408211	SCV000381456	likely benign	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 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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000442189	SCV000511628	likely benign	not provided	2016-09-15	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082252	SCV000554515	benign	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000442189	SCV000566049	likely benign	not provided	2020-01-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28127548, 27166760)
CeGaT Center for Human Genetics Tuebingen	RCV000442189	SCV000780444	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	CEP290: BP4, BS2
Genome-Nilou Lab	RCV000408211	SCV001781512	uncertain significance	Bardet-Biedl syndrome 14	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000351974	SCV001781513	uncertain significance	Joubert syndrome 5	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000402012	SCV001781514	uncertain significance	Meckel syndrome, type 4	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000366483	SCV001781515	uncertain significance	Senior-Loken syndrome 6	2021-07-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000082249	SCV002500532	likely benign	not specified	2022-03-20	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.4237G>C (p.Asp1413His) results in a non-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 0.0023 in 229244 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 2.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in CEP290 causing Meckel Syndrome Type 4 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no penetrant association of c.4237G>C in individuals affected with Meckel Syndrome Type 4 and no experimental evidence demonstrating its impact on protein function have been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as likely benign/benign (n=6) (VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004528298	SCV000314551	likely benign	CEP290-related disorder	2023-02-10	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001273070	SCV001455657	likely benign	Leber congenital amaurosis	2020-04-17	no assertion criteria provided	clinical testing