ClinVar Miner

Submissions for variant NM_152443.3(RDH12):c.226G>C (p.Gly76Arg)

gnomAD frequency: 0.00001  dbSNP: rs368489658
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001387782 SCV001588498 pathogenic Leber congenital amaurosis 13 2023-08-09 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1074472). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 76 of the RDH12 protein (p.Gly76Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal recessive RDH12-related conditions (PMID: 19956407, 24265693, 30134391, 30372751). It has also been observed to segregate with disease in related individuals. 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 RDH12 protein function. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV001387782 SCV002019038 likely pathogenic Leber congenital amaurosis 13 2020-03-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001831398 SCV004038781 pathogenic Leber congenital amaurosis 2023-08-21 criteria provided, single submitter clinical testing Variant summary: RDH12 c.226G>C (p.Gly76Arg) 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 was absent in 251494 control chromosomes (gnomAD). c.226G>C has been reported in the literature in bi-allelic individuals affected with Leber Congenital Amaurosis and autosomal recessive Retinitis pigmentosa (examples: Aldahmesh_2009, Eisenberger_2013, Aleman_2018, and Jin_2022). These data indicate that the variant is likely to be associated with disease. A different variant resulting in the same amino acid change (c.226G>A, p.Gly76Arg) has been reported in bi-allelic individuals affected with Leber Congenital Amaurosis and autosomal recessive Retinitis pigmentosa (PMID: 35006499) and is classified as pathogenic in ClinVar (ID 986946). The following publications have been ascertained in the context of this evaluation (PMID: 19956407, 30372751, 24265693, 35006499). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Dr.Nikuei Genetic Center RCV001387782 SCV005200344 pathogenic Leber congenital amaurosis 13 2024-07-10 criteria provided, single submitter clinical testing
Natera, Inc. RCV001831398 SCV002091258 pathogenic Leber congenital amaurosis 2020-12-10 no assertion criteria provided clinical testing

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