ClinVar Miner

Submissions for variant NM_152443.3(RDH12):c.869T>G (p.Val290Gly)

gnomAD frequency: 0.00029  dbSNP: rs61740289
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000293076 SCV000338138 uncertain significance not provided 2015-12-10 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001041798 SCV001205438 pathogenic Leber congenital amaurosis 13 2024-11-22 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 290 of the RDH12 protein (p.Val290Gly). This variant is present in population databases (rs61740289, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of autosomal recessive RDH12-related conditions (PMID: 24265693, 25910913; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285209). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RDH12 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075352 SCV001240973 likely pathogenic Retinal dystrophy 2018-05-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155148 SCV003844436 uncertain significance not specified 2023-02-07 criteria provided, single submitter clinical testing Variant summary: RDH12 c.869T>G (p.Val290Gly) 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 6.8e-05 in 251440 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in RDH12 causing Leber Congenital Amaurosis (6.8e-05 vs 0.0016), allowing no conclusion about variant significance. c.869T>G has been reported in the literature in individuals affected with RDH12 related conditions (examples: Eisenberger_2013 and Lee_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV001041798 SCV004208569 likely pathogenic Leber congenital amaurosis 13 2024-03-30 criteria provided, single submitter clinical testing
Natera, Inc. RCV001277208 SCV001464107 uncertain significance Leber congenital amaurosis 2020-09-16 no assertion criteria provided clinical testing

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