Submissions for variant NM_001297.5(CNGB1):c.290+2T>C

gnomAD frequency: 0.00001  dbSNP: rs1429797650

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377501	SCV001574845	likely pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 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 (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with clinical features of CNGB1-related conditions (PMID: 36460718; internal data). ClinVar contains an entry for this variant (Variation ID: 1066490). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323871	SCV004029293	likely pathogenic	Retinitis pigmentosa	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: CNGB1 c.290+2T>C 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: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249056 control chromosomes. c.290+2T>C has been reported in the literature as a non-informative genotype (carrier without a second allele) in an individual affected with Choroideremia (Corvi_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.