Submissions for variant NM_025114.4(CEP290):c.7220_7223del (p.Lys2407fs)

dbSNP: rs763762899

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485275	SCV000564862	likely pathogenic	not provided	2018-06-13	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the CEP290 gene. The c.7220_7223delAGAA variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.7220_7223delAGAA variant causes a frameshift starting with codon Lysine 2407, changes this amino acid to a Serine residue and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Lys2407SerfsX2. This variant is predicted to cause loss of normal protein function through protein truncation. The c.7220_7223delAGAA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV001238421	SCV001411229	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys2407Serfs*2) in the CEP290 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the CEP290 protein. This variant is present in population databases (rs763762899, gnomAD 0.01%). 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: 418123). This variant disrupts a region of the CEP290 protein in which other variant(s) (p.Leu2448Thrfs*8) have been determined to be pathogenic (PMID: 16682973, 16909394, 29588463). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270057	SCV001448793	likely pathogenic	Global developmental delay; Micrognathia; Abnormal facial shape; Hypotonia	2019-12-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470523	SCV004216518	likely pathogenic	Bardet-Biedl syndrome 14	2023-09-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003960123	SCV004767087	pathogenic	CEP290-related condition	2023-11-05	criteria provided, single submitter	clinical testing	The CEP290 c.7220_7223delAGAA variant is predicted to result in a frameshift and premature protein termination (p.Lys2407Serfs*2). To our knowledge, this variant has not been reported in association with disorders in the literature. This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-88443177-CTTCT-C). This variant is located within the terminal exon and multiple downstream truncating variants have been documented to be causative for CEP290-associated disorders (Human Gene Mutation Database). Frameshift variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987554	SCV004804161	pathogenic	Meckel syndrome, type 4	2024-01-04	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.7220_7223delAGAA (p.Lys2407SerfsX2) results in a premature termination codon and although it is not expected to cause absence of the protein due to nonsense mediated decay, it is predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.1e-05 in 190972 control chromosomes (gnomAD). To our knowledge, no occurrence of c.7220_7223delAGAA in individuals affected with Meckel Syndrome Type 4 or other CEP290-related disorders and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.