Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025114.4(CEP290):c.6869_6870insA(p.Asn2290LysfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,401,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N2290N) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
CEP290 (HGNC:29021): (centrosomal protein 290) This gene encodes a protein with 13 putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. Mutations in this gene have been associated with Joubert syndrome and nephronophthisis and the presence of antibodies against this protein is associated with several forms of cancer. [provided by RefSeq, Jul 2008]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-88055666-A-AT is Pathogenic according to our data. Variant chr12-88055666-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 156386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jun 30, 2022
Variant summary: CEP290 c.6869dupA (p.Asn2290LysfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00027 in 161872 control chromosomes. c.6869dupA has been reported in the literature in individuals affected with CEP290-Related Disorders. These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Leber congenital amaurosis 10 Pathogenic:1
Pathogenic, no assertion criteria provided
clinical testing
Molecular Diagnostics Laboratory, Seoul National University Hospital
Sep 18, 2014
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Leber congenital amaurosis Pathogenic:1
Pathogenic, no assertion criteria provided
clinical testing
Natera, Inc.
Sep 16, 2020
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Bardet-Biedl syndrome 14 Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Oct 16, 2023
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Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis;C0687120:Nephronophthisis Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Nov 24, 2023
This sequence change creates a premature translational stop signal (p.Asn2290Lysfs*6) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 25445212). This variant is also known as c.6869_6870insA. ClinVar contains an entry for this variant (Variation ID: 156386). For these reasons, this variant has been classified as Pathogenic. -