Submissions for variant NM_001297.5(CNGB1):c.2285G>A (p.Arg762His)

gnomAD frequency: 0.00001  dbSNP: rs760373259

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524402	SCV003443655	pathogenic	not provided	2022-12-31	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg762 amino acid residue in CNGB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21987686, 24339724, 29202463). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 762 of the CNGB1 protein (p.Arg762His). This variant is present in population databases (rs760373259, gnomAD 0.006%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 28041643, 30718709, 31570810). ClinVar contains an entry for this variant (Variation ID: 437972). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CNGB1 protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504924	SCV004020820	likely pathogenic	Retinitis pigmentosa	2023-06-29	criteria provided, single submitter	clinical testing	Variant summary: CNGB1 c.2285G>A (p.Arg762His) results in a non-conservative amino acid change in the encoded protein sequence, altering a highly conserved residue (HGMD) in which another missense variant (p.Arg762Cys) has been classified as pathogenic (ClinVar). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249018 control chromosomes (gnomAD). c.2285G>A has been reported in the literature in homozygous individuals affected with Retinitis Pigmentosa (e.g. Carss_2017, Jespersgaard_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32581362, 28041643, 31570810, 35743231, 30718709). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=2) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989545	SCV004808092	pathogenic	Retinitis pigmentosa 45	2024-03-29	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504924	SCV000598710	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000504924	SCV000926832	uncertain significance	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research