ClinVar Miner

Submissions for variant NM_019098.5(CNGB3):c.680T>C (p.Leu227Pro)

gnomAD frequency: 0.00001  dbSNP: rs752920111
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001305799 SCV001495147 uncertain significance not provided 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 227 of the CNGB3 protein (p.Leu227Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs752920111, ExAC 0.05%). This missense change has been observed in individual(s) with cone-rod dystrophy (PMID: 26992781). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
3billion RCV002250749 SCV002521442 uncertain significance Achromatopsia 3 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Protein truncation variants are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CNGB3 related disorder (PMID: 26992781). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003331099 SCV004038334 uncertain significance not specified 2023-08-07 criteria provided, single submitter clinical testing Variant summary: CNGB3 c.680T>C (p.Leu227Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251368 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CNGB3 causing Achromatopsia (4e-05 vs 0.005), allowing no conclusion about variant significance. c.680T>C has been reported in the literature in individuals affected with cone-rod dystrophy (Huang_2016, Sun_2020). These data indicate that the variant may 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: 26992781, 32913385). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Natera, Inc. RCV001279842 SCV001466973 uncertain significance Achromatopsia 2020-10-05 no assertion criteria provided clinical testing

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