14-67727056-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_152443.3(RDH12):c.524C>T(p.Ser175Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S175P) has been classified as Pathogenic.
Frequency
Consequence
NM_152443.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RDH12 | NM_152443.3 | c.524C>T | p.Ser175Leu | missense_variant | 7/9 | ENST00000551171.6 | |
RDH12 | XM_047430965.1 | c.524C>T | p.Ser175Leu | missense_variant | 7/9 | ||
GPHN | XM_047430879.1 | c.1313-8139C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RDH12 | ENST00000551171.6 | c.524C>T | p.Ser175Leu | missense_variant | 7/9 | 1 | NM_152443.3 | P1 | |
RDH12 | ENST00000267502.3 | c.524C>T | p.Ser175Leu | missense_variant | 6/8 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251460Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135910
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461708Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727162
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152318Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74480
ClinVar
Submissions by phenotype
Leber congenital amaurosis 13 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 29, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Ocular Genomics Institute, Massachusetts Eye and Ear | Aug 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 08, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 29, 2020 | The heterozygous p.Ser175Leu variant in RDH12 was identified by our study in 1 individual with Leber congenital amaurosis, along with a variant of uncertain significance. Please note that this variant has been identified by a collaborative research study and was also be submitted by Massachusetts Eye and Ear (PMID: 32014858). The p.Ser175Leu variant has been reported, in trans with another likely pathogenic variant, in 1 additional individual with Leber congenital amaurosis (PMID: 20683928). This variant has been identified in 0.004% (1/24970) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs116733939). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic by Invitae and likely pathogenic by Cytogenetics and Genomics Laboratory, Medical University of South Carolina and Ocular Genomics Institute, Massachusetts Eye and Ear (Variation ID: 559527). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Ser175Leu variant is located in a region of RDH12 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 20683928). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PP3, PM1_supporting (Richards 2015). - |
Pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 175 of the RDH12 protein (p.Ser175Leu). This variant is present in population databases (rs116733939, gnomAD 0.005%). This missense change has been observed in individuals with autosomal recessive Leber congenital amaurosis (PMID: 20683928, 22065924, 30134391). ClinVar contains an entry for this variant (Variation ID: 559527). 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 with a positive predictive value of 80%. This variant disrupts the p.Ser175 amino acid residue in RDH12. Other variant(s) that disrupt this residue have been observed in individuals with RDH12-related conditions (PMID: 15322982), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2022 | 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: 30870047, 20683928, 22065924, 24123792, 27208204, 30134391, 32014858, 34001834, 35006499) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Leber congenital amaurosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Cytogenetics and Genomics Laboratory, Medical University of South Carolina | Jun 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at