ClinVar Miner

Submissions for variant NM_001297.5(CNGB1):c.2603G>A (p.Gly868Asp)

gnomAD frequency: 0.00001  dbSNP: rs770961534
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000585175 SCV000692858 uncertain significance not provided 2017-10-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory, Institute for Ophthalmic Research RCV001119757 SCV001162474 pathogenic Retinitis pigmentosa 2020-01-09 criteria provided, single submitter research
Illumina Laboratory Services, Illumina RCV001119757 SCV001278196 uncertain significance Retinitis pigmentosa 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000585175 SCV001517208 pathogenic not provided 2023-12-09 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 868 of the CNGB1 protein (p.Gly868Asp). This variant is present in population databases (rs770961534, gnomAD 0.002%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 32613137; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 493184). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000585175 SCV003805124 uncertain significance not provided 2022-08-19 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 33847019, 32613137)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001119757 SCV004223221 pathogenic Retinitis pigmentosa 2023-11-28 criteria provided, single submitter clinical testing Variant summary: CNGB1 c.2603G>A (p.Gly868Asp) results in a non-conservative amino acid change in the encoded protein sequence. 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 8e-06 in 249582 control chromosomes (gnomAD). c.2603G>A has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa (Alshamrani_2020, Weisschuh_2020, Nassisi_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32613137, 32531858, 33847019). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=2) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.

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