Submissions for variant NM_019098.4(CNGB3):c.467C>T (p.Ser156Phe) (rs139207764)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000498220	SCV000795326	uncertain significance	Achromatopsia 3	2017-11-03	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000498220	SCV000916239	likely pathogenic	Achromatopsia 3	2018-12-14	criteria provided, single submitter	clinical testing	The CNGB3 c.467C>T (p.Ser156Phe) missense variant has been reported in three studies and identified in at least four unrelated compound heterozygotes, all affected with achromatopsia (Kohl et al. 2005; Zein et al. 2014; Zelinger et al. 2015). The variant was absent from 100 healthy controls but is reported at a frequency of 0.000394 in the Ashkenazi Jewish population in the Genome Aggregation Database. Meighan et al. (2015) performed functional studies using Xenopus oocytes and the p.Ser156Phe variant was found not to interfere with the formation of functional A3+B3 channels or to cause significant changes to CNG channel behavior compared to wild type. The variant is not found in a highly conserved region of the protein (Meighan et al. 2015). Based on the evidence, the p.Ser156Phe variant is classified as likely pathogenic for achromatopsia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute for Ophthalmic Research,University Tuebingen	RCV000498220	SCV000575805	likely pathogenic	Achromatopsia 3	2017-03-27	no assertion criteria provided	research
Invitae	RCV000815424	SCV000955875	likely pathogenic	not provided	2018-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces serine with phenylalanine at codon 156 of the CNGB3 protein (p.Ser156Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs139207764, ExAC 0.01%). This variant has been observed in individuals with achromatopsia (PMID: 25616768, 15657609, 28795510). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 427671). This variant has been reported to have insufficient data to determine the effect on CNGB3 protein function (PMID: 26106334). 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.