Submissions for variant NM_001297.5(CNGB1):c.1801+5G>A

gnomAD frequency: 0.00004  dbSNP: rs375550800

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002612331	SCV003513393	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with retinitis pigmentosa (PMID: 28981474). This variant is present in population databases (rs375550800, gnomAD 0.004%). This sequence change falls in intron 19 of the CNGB1 gene. It does not directly change the encoded amino acid sequence of the CNGB1 protein. It affects a nucleotide within the consensus splice site.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155516	SCV003844895	uncertain significance	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: CNGB1 c.1801+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four 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 2.4e-05 in 249446 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1801+5G>A has been reported in the literature in individuals affected with Retinitis Pigmentosa (example: Comander_2017). 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 clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.