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

Total submissions: 26

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