Submissions for variant NM_019098.5(CNGB3):c.1578+1G>A

gnomAD frequency: 0.00002  dbSNP: rs372006750

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169421	SCV000220830	likely pathogenic	Achromatopsia 3	2014-10-22	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000724126	SCV000225904	pathogenic	not provided	2014-10-17	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV000592120	SCV000700213	pathogenic	Achromatopsia	2018-03-20	criteria provided, single submitter	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000169421	SCV001366575	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,PM2,PM3,PP3,PP5.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000724126	SCV001447843	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV000169421	SCV001548063	likely pathogenic	Achromatopsia 3	2021-01-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724126	SCV001586086	pathogenic	not provided	2024-07-09	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 13 of the CNGB3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CNGB3 are known to be pathogenic (PMID: 28795510). This variant is present in population databases (rs372006750, gnomAD 0.004%). Disruption of this splice site has been observed in individuals with achromatopsia (PMID: 10958649, 12187429). ClinVar contains an entry for this variant (Variation ID: 189031). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000724126	SCV001962144	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	CNGB3: PM3:Very Strong, PVS1, PM2
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000169421	SCV002577448	pathogenic	Achromatopsia 3	2022-09-23	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Fulgent Genetics, Fulgent Genetics	RCV000169421	SCV002807450	pathogenic	Achromatopsia 3	2024-06-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000169421	SCV004235032	pathogenic	Achromatopsia 3	2023-03-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815260	SCV005072342	pathogenic	Retinal dystrophy	2021-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000724126	SCV005078070	pathogenic	not provided	2024-07-08	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24148654, 25558176, 12187429, 31429209, 32531858, 35456422, 25525159, 10958649, 28795510, 31589614, 32037395, 34449556, 31964843, 37734845, 36460718, 34321860, 15657609)
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV000169421	SCV000575851	pathogenic	Achromatopsia 3	2017-03-27	no assertion criteria provided	research
Natera, Inc.	RCV000592120	SCV002076069	pathogenic	Achromatopsia	2020-03-22	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004539570	SCV004775171	pathogenic	CNGB3-related disorder	2024-02-26	no assertion criteria provided	clinical testing	The CNGB3 c.1578+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous or compound heterozygous state in individuals with achromatopsia (see, for example, Kohl et al. 2000. PubMed ID: 10958649; Burkard et al. 2018. PubMed ID: 30418171, supplementary data). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/). Variants that disrupt the consensus splice donor site in CNGB3 are expected to be pathogenic. This variant is interpreted as pathogenic.