ClinVar Miner

Submissions for variant NM_152443.3(RDH12):c.295C>A (p.Leu99Ile)

gnomAD frequency: 0.00004  dbSNP: rs28940315
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000594844 SCV000701365 pathogenic not provided 2016-10-21 criteria provided, single submitter clinical testing
Invitae RCV000002136 SCV000767478 pathogenic Leber congenital amaurosis 13 2023-12-31 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 99 of the RDH12 protein (p.Leu99Ile). This variant is present in population databases (rs28940315, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive Leber congenital amaurosis, early-onset retinal degeneration and/or retinal dystrophy (PMID: 15322982, 22065924, 24474277, 26306921). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2055). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RDH12 protein function. Experimental studies have shown that this missense change affects RDH12 function (PMID: 16269441). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000002136 SCV001139477 pathogenic Leber congenital amaurosis 13 2019-05-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075855 SCV001241494 pathogenic Retinal dystrophy 2019-08-08 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV000002136 SCV001573615 pathogenic Leber congenital amaurosis 13 2021-04-08 criteria provided, single submitter research The RDH12 c.295C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PS3, PP1-M. Based on this evidence we have classified this variant as Pathogenic.
GeneDx RCV000594844 SCV001802381 pathogenic not provided 2023-09-13 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: reduced ability to convert all-trans retinal to all-trans retinol in the presence of NADPH, with roughly 10% catalytic activity compared to wild type (Thompson et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27032803, 27596865, 31814694, 26667666, 32141364, 23900199, 22995991, 15322982, 22065924, 21151602, 24474277, 26306921, 16269441, 26261414, 19011012, 31456290, 32036094, 31589614, 32865313, 34448047)
3billion RCV000002136 SCV002058844 pathogenic Leber congenital amaurosis 13 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002055, PMID:15322982, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 15322982, 27032803, PM3_M). The variant was co-segregated with Leber congenital amaurosis 13 in multiple affected family members (PMID: 15322982, 27032803, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.676, 3CNET: 0.93, PP3_P). A missense variant is a common mechanism associated with Leber congenital amaurosis 13 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000060, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001277202 SCV002556303 pathogenic Leber congenital amaurosis 2022-06-02 criteria provided, single submitter clinical testing Variant summary: RDH12 c.295C>A (p.Leu99Ile) results in a 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 6.4e-05 in 251488 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RDH12 causing Leber Congenital Amaurosis (6.4e-05 vs 0.0016), allowing no conclusion about variant significance. c.295C>A has been reported in the literature in multiple individuals affected with retinal diseases. These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center RCV000002136 SCV002580404 likely pathogenic Leber congenital amaurosis 13 2021-10-06 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000002136 SCV002814438 pathogenic Leber congenital amaurosis 13 2021-11-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV000002136 SCV004208567 pathogenic Leber congenital amaurosis 13 2023-10-06 criteria provided, single submitter clinical testing
OMIM RCV000002136 SCV000022294 pathogenic Leber congenital amaurosis 13 2004-10-01 no assertion criteria provided literature only
Ocular Genomics Institute, Massachusetts Eye and Ear RCV000993758 SCV001146952 pathogenic Retinitis pigmentosa 2019-08-01 no assertion criteria provided clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center RCV000993758 SCV001161223 pathogenic Retinitis pigmentosa 2019-06-23 no assertion criteria provided research
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV000002136 SCV001432271 pathogenic Leber congenital amaurosis 13 no assertion criteria provided research
Natera, Inc. RCV001277202 SCV001464101 pathogenic Leber congenital amaurosis 2020-09-16 no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV000002136 SCV004228927 not provided Leber congenital amaurosis 13 no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 02-25-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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