Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001201454 | SCV001372522 | pathogenic | Retinitis pigmentosa 12; Leber congenital amaurosis 8 | 2023-12-10 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 614 of the CRB1 protein (p.Gly614Val). This variant is present in population databases (rs763111500, gnomAD 0.03%). This missense change has been observed in individual(s) with retinitis pigementosa or Leber congenital amaurosis (PMID: 23661368, 24535598, 27806333, 29641573). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 933277). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRB1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
3billion | RCV002250730 | SCV002521082 | pathogenic | Leber congenital amaurosis 8 | 2022-05-22 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.57). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 23661368, 24535598). and also reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID:23661368). A different missense change at the same codon (p.Gly614Asp) has been reported to be associated with CRB1 related disorder (PMID: 30029497). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003230647 | SCV003928747 | pathogenic | Retinal dystrophy | 2023-04-26 | criteria provided, single submitter | clinical testing | Variant summary: CRB1 c.1841G>T (p.Gly614Val) results in a non-conservative amino acid change altering a highly conserved residue located in the Laminin G domain (IPR001791) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251240 control chromosomes (gnomAD). c.1841G>T has been reported in the literature in multiple individuals affected with Retinal degeneration or retinitis pigmentosa with evidence of cosegregation with disease, and some were compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33342761, 27806333, 25377065). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Genome- |
RCV002250730 | SCV004179976 | pathogenic | Leber congenital amaurosis 8 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV003449640 | SCV004179977 | pathogenic | Pigmented paravenous retinochoroidal atrophy | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV003449639 | SCV004179978 | pathogenic | Retinitis pigmentosa 12 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV002250730 | SCV004211180 | pathogenic | Leber congenital amaurosis 8 | 2023-07-05 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV001833768 | SCV002090149 | pathogenic | Leber congenital amaurosis | 2020-06-03 | no assertion criteria provided | clinical testing |