ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs760373259
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002524402 SCV003443655 pathogenic not provided 2022-12-31 criteria provided, single submitter clinical testing This missense change has been observed in individuals with retinitis pigmentosa (PMID: 28041643, 30718709, 31570810). This variant is present in population databases (rs760373259, gnomAD 0.006%). 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). ClinVar contains an entry for this variant (Variation ID: 437972). For these reasons, this variant has been classified as Pathogenic. 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. 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.
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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center 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

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