Total submissions: 31
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
EGL Genetic Diagnostics, |
RCV000081978 | SCV000225048 | pathogenic | not provided | 2017-02-05 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000081978 | SCV000329303 | pathogenic | not provided | 2018-08-30 | criteria provided, single submitter | clinical testing | The c.1148delC pathogenic variant in the CNGB3 gene has been reported previously in the homozygous and compound heterozygous states in individuals with autosomal recessive achromatopsia and accounts for over 70-75% of all CNGB3 mutant alleles (Sundin et al., 2000; Kohl et al., 2005; Wiszniewski et al., 2007). The deletion causes a frameshift starting with codon Threonine 383, changes this amino acid to an Isoleucine residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Thr383IlefsX13.This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies have shown that if a truncated CNGB3 protein is produced, then the resultant CNG channel complex leads to abnormal cone photoreceptor function (Peng et al., 2003; Liu et al., 2013). The c.1148delC variant is observed in 487/276,004 (0.176%) total alleles in large population cohorts and two individuals were reported to be homozygous (Lek et al., 2016). In summary, we interpret c.1148delC as a pathogenic variant. |
Illumina Clinical Services Laboratory, |
RCV000273066 | SCV000475214 | uncertain significance | Stargardt Disease, Recessive | 2016-06-14 | criteria provided, single submitter | clinical testing | |
Illumina Clinical Services Laboratory, |
RCV000778111 | SCV000475215 | pathogenic | CNGB3-Related Disorders | 2018-05-07 | criteria provided, single submitter | clinical testing | The CNGB3 c.1148delC (p.Thr383IlefsTer13) variant results in a frameshift and is predicted to result in a premature termination of the protein. The p.Thr383IlefsTer13 variant has not been reported in the literature in individuals with Stargardt disease but is described as the most common pathogenic variant accounting for over 70% of all CNGB3 disease-causing alleles and approximately 40% of all achromatopsia-associated alleles (Wiszniewski et al 2007; Aboshiha et al. 2016). Across a selection of the available literature the p.Thr383IlefsTer13 variant is found in a total of 406 patients including 112 in a homozygous state, 41 in a compound heterozygous state, and eight in a heterozygous state (Sundin et al. 2000; Nishiguchi et al. 2005; Kohl et al. 2005; Wiszniewski et al. 2007). The p.Thr383IlefsTer13 variant showed segregation with disease. The variant was absent from 146 controls but is reported at a frequency of 0.00339 in the European American population of the Exome Sequencing Project. Wiszniewski et al. (2007) used haplotype analysis to demonstrate a founder effect among individuals of European ancestry for the variant thus explaining the high frequency. Functional studies showed that the p.Thr383IlefsTer13 variant resulted in a gain-of-function with enhanced channel activity and an increased sensitivity to cell death compared to wild type (Bright et al. 2005; Liu et al. 2013). Expression studies in Xenopus oocytes demonstrated that the p.Thr383IlefsTer13 variant failed to produce a CNGB3 subunit sufficient for normal cone photoreceptor function, and is essentially a null variant (Peng et al. 2003). Due to the potential impact of frameshift variants and the collective evidence from the literature, the p.Thr383IlefsTer13 variant is classified as a pathogenic variant for CNGB3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
Counsyl | RCV000005535 | SCV000678134 | pathogenic | Achromatopsia 3 | 2015-07-29 | criteria provided, single submitter | clinical testing | |
Institute for Ophthalmic Research, |
RCV000328174 | SCV000700211 | pathogenic | Achromatopsia | 2018-03-20 | criteria provided, single submitter | research | |
Laboratory for Molecular Medicine, |
RCV000328174 | SCV000711739 | pathogenic | Achromatopsia | 2015-12-07 | criteria provided, single submitter | clinical testing | The p.Thr383IlefsX13 (or p.Thr383fsX) (NM_019098.4 c.1148delC) variant in CNGB3 has been reported in >100 individuals with achromatopsia and was the most common CNGB3 variant identified in patients with this disease (Kohl 2003, Sundin 2010) . The reported patients were either homozygous or compound heterozygous with ano ther CNGB3 variant. This variant has been identified in 0.3% (187/66554) of Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs397515360). Please note that for diseases with recessive inh eritance, clinical variability, or reduced penetrance pathogenic variants may be present at a low frequency in the general population. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 383 and leads to a premature termination codon 13 amino acids downs tream. This alteration is then predicted to lead to a truncated or absent protei n. Loss of function of the CNGB3 gene is an established disease mechanism in ind ividuals with achromatopsia. In summary, this variant meets our criteria to be c lassified as pathogenic for achromatopsia in an autosomal recessive manner based upon its segregation in affected individuals and predicted impact on protein fu nction. |
Invitae | RCV000081978 | SCV000940860 | pathogenic | not provided | 2020-01-07 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Thr383Ilefs*13) in the CNGB3 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs397515360, ExAC 0.3%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant is the most common cause of achromatopsia in Europe and has been observed to segregate with the disease in several families (PMID: 10888875, 10958649, 15657609, 15712225, 17265047). ClinVar contains an entry for this variant (Variation ID: 5225). Loss-of-function variants in CNGB3 are known to be pathogenic (PMID: 15657609). For these reasons, this variant has been classified as Pathogenic. |
Ocular Genomics Institute, |
RCV000005535 | SCV001142655 | pathogenic | Achromatopsia 3 | 2019-09-18 | criteria provided, single submitter | research | |
Blueprint Genetics | RCV000504902 | SCV001239931 | pathogenic | Retinal dystrophy | 2019-07-22 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000081978 | SCV001245904 | pathogenic | not provided | 2019-02-01 | criteria provided, single submitter | clinical testing | |
Centre for Mendelian Genomics, |
RCV000005535 | SCV001366576 | pathogenic | Achromatopsia 3 | 2016-01-01 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM3,PP4,PP5. |
Centogene AG - |
RCV000005535 | SCV001426610 | pathogenic | Achromatopsia 3 | criteria provided, single submitter | clinical testing | ||
Institute of Human Genetics, |
RCV000005535 | SCV001428772 | pathogenic | Achromatopsia 3 | 2019-09-24 | criteria provided, single submitter | clinical testing | This variant was identified as homozygous |
Institute of Medical Genetics and Applied Genomics, |
RCV000081978 | SCV001447252 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000005535 | SCV000025717 | pathogenic | Achromatopsia 3 | 2007-05-01 | no assertion criteria provided | literature only | |
Gene |
RCV000005535 | SCV000086982 | pathologic | Achromatopsia 3 | 2013-06-27 | no assertion criteria provided | curation | Converted during submission to Pathogenic. |
Institute for Ophthalmic Research, |
RCV000005535 | SCV000575789 | pathogenic | Achromatopsia 3 | 2017-03-27 | no assertion criteria provided | research | |
NIHR Bioresource Rare Diseases, |
RCV000504902 | SCV000598859 | pathogenic | Retinal dystrophy | 2015-01-01 | no assertion criteria provided | research | |
NIHR Bioresource Rare Diseases, |
RCV000328174 | SCV000598860 | pathogenic | Achromatopsia | 2015-01-01 | no assertion criteria provided | research | |
NIHR Bioresource Rare Diseases, |
RCV000504797 | SCV000598861 | pathogenic | Abnormality of the eye | 2015-01-01 | no assertion criteria provided | research | Undetermined rare ocular disorder with frequency of less than eight patients |
NIHR Bioresource Rare Diseases, |
RCV000505026 | SCV000598862 | pathogenic | Leber congenital amaurosis | 2015-01-01 | no assertion criteria provided | research | |
Human Genetics - |
RCV000505026 | SCV000804623 | pathogenic | Leber congenital amaurosis | 2016-09-01 | no assertion criteria provided | clinical testing | |
Medical Genetics Laboratory, |
RCV000787571 | SCV000926549 | pathogenic | Cone-rod dystrophy | 2018-04-01 | no assertion criteria provided | research | |
Medical Genetics Laboratory, |
RCV000328174 | SCV000926550 | pathogenic | Achromatopsia | 2018-04-01 | no assertion criteria provided | research | |
Medical Genetics Laboratory, |
RCV000505026 | SCV000926551 | pathogenic | Leber congenital amaurosis | 2018-04-01 | no assertion criteria provided | research | |
Medical Genetics Laboratory, |
RCV000787822 | SCV000926835 | pathogenic | Retinitis pigmentosa | 2018-04-01 | no assertion criteria provided | research | |
Biesecker Lab/Clinical Genomics Section, |
RCV000005535 | SCV001132528 | pathogenic | Achromatopsia 3 | 2014-03-06 | no assertion criteria provided | curation | |
Sharon lab, |
RCV000328174 | SCV001161029 | pathogenic | Achromatopsia | 2019-06-23 | no assertion criteria provided | research | |
Laboratory of Genetics in Ophthalmology, |
RCV000005535 | SCV001450762 | pathogenic | Achromatopsia 3 | no assertion criteria provided | research | ||
Natera, |
RCV000328174 | SCV001454548 | pathogenic | Achromatopsia | 2020-09-16 | no assertion criteria provided | clinical testing |