Submissions for variant NM_025114.4(CEP290):c.2174A>C (p.Glu725Ala)

gnomAD frequency: 0.00005  dbSNP: rs375038986

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000310425	SCV000381557	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	RCV000365084	SCV000381558	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	RCV000400672	SCV000381559	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	RCV000307295	SCV000381560	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	RCV000371328	SCV000381561	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000861492	SCV001001825	likely benign	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001562789	SCV001785614	uncertain significance	not provided	2023-07-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported with a second variant (phase unknown) in a patient with ataxia in published literature (Hamed et al., 2020); This variant is associated with the following publications: (PMID: 32443735, 31970223)
New York Genome Center	RCV002467728	SCV002764472	uncertain significance	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5	2021-12-10	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV003888723	SCV004707693	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Department of Pediatrics, Samsung Medical Center, Samsung Medical Center	RCV001252733	SCV001163876	uncertain significance	Microcephaly		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732842	SCV005365261	uncertain significance	CEP290-related disorder	2024-06-23	no assertion criteria provided	clinical testing	The CEP290 c.2174A>C variant is predicted to result in the amino acid substitution p.Glu725Ala. This variant has been reported in the compound heterozygous state in an individual with episodic ataxia (Hamed et al. 2020. PubMed ID: 31970223). This variant is reported in 0.27% of alleles in individuals of East Asian descent in gnomAD, which is more frequent than expected for a pathogenic variant. 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.