Submissions for variant NM_001297.5(CNGB1):c.2794+1G>A

gnomAD frequency: 0.00009  dbSNP: rs770011113

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000487966	SCV000575055	likely pathogenic	not provided	2017-01-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV001199466	SCV001162475	pathogenic	Retinitis pigmentosa	2020-01-09	criteria provided, single submitter	research
Blueprint Genetics	RCV001074635	SCV001240227	likely pathogenic	Retinal dystrophy	2019-02-06	criteria provided, single submitter	clinical testing
Invitae	RCV000487966	SCV001408362	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 27 of the CNGB1 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 CNGB1 are known to be pathogenic (PMID: 15557452, 24043777). This variant is present in population databases (rs770011113, gnomAD 0.06%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 425109). Disruption of this splice site has been observed in individuals with clinical features of retinitis pigmentosa (PMID: 33847019; Invitae).
DBGen Ocular Genomics	RCV001725185	SCV001960893	pathogenic	Retinitis pigmentosa 45	2021-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199466	SCV004242021	pathogenic	Retinitis pigmentosa	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: CNGB1 c.2794+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 9.2e-05 in 249286 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CNGB1 causing Retinitis Pigmentosa (9.2e-05 vs 0.00063), allowing no conclusion about variant significance. c.2794+1G>A has been reported in the literature in individuals affected with Retinitis Pigmentosa (eg. Weisschuh_2020). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.