ClinVar Miner

Submissions for variant NM_019098.4(CNGB3):c.1148del (p.Thr383fs) (rs397515360)

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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081978 SCV000225048 pathogenic not provided 2017-02-05 criteria provided, single submitter clinical testing
GeneDx 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,Illumina RCV000273066 SCV000475214 uncertain significance Stargardt Disease, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina 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,University Tuebingen RCV000328174 SCV000700211 pathogenic Achromatopsia 2018-03-20 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized 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,Massachusetts Eye and Ear 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
CeGaT Praxis fuer Humangenetik Tuebingen RCV000081978 SCV001245904 pathogenic not provided 2019-02-01 criteria provided, single submitter clinical testing
OMIM RCV000005535 SCV000025717 pathogenic Achromatopsia 3 2007-05-01 no assertion criteria provided literature only
OMIM RCV000005536 SCV000025718 pathogenic Stargardt disease 1 2007-05-01 no assertion criteria provided literature only
GeneReviews RCV000005535 SCV000086982 pathologic Achromatopsia 3 2013-06-27 no assertion criteria provided curation Converted during submission to Pathogenic.
Institute for Ophthalmic Research,University Tuebingen RCV000005535 SCV000575789 pathogenic Achromatopsia 3 2017-03-27 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504902 SCV000598859 pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000328174 SCV000598860 pathogenic Achromatopsia 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge 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, University of Cambridge RCV000505026 SCV000598862 pathogenic Leber congenital amaurosis 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000505026 SCV000804623 pathogenic Leber congenital amaurosis 2016-09-01 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787571 SCV000926549 pathogenic Cone-rod dystrophy 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000328174 SCV000926550 pathogenic Achromatopsia 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000505026 SCV000926551 pathogenic Leber congenital amaurosis 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787822 SCV000926835 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000005535 SCV001132528 pathogenic Achromatopsia 3 2014-03-06 no assertion criteria provided curation
Sharon lab,Hadassah-Hebrew University Medical Center RCV000328174 SCV001161029 pathogenic Achromatopsia 2019-06-23 no assertion criteria provided research

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