rs104893768
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000539.3(RHO):c.68C>A(p.Pro23His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P23L) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
RHO
NM_000539.3 missense
NM_000539.3 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.90
Genes affected
RHO (HGNC:10012): (rhodopsin) The protein encoded by this gene is found in rod cells in the back of the eye and is essential for vision in low-light conditions. The encoded protein binds to 11-cis retinal and is activated when light hits the retinal molecule. Defects in this gene are a cause of congenital stationary night blindness. [provided by RefSeq, Aug 2017]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
In a topological_domain Extracellular (size 35) in uniprot entity OPSD_HUMAN there are 36 pathogenic changes around while only 0 benign (100%) in NM_000539.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 3-129528801-C-A is Pathogenic according to our data. Variant chr3-129528801-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 13013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129528801-C-A is described in Lovd as [Pathogenic]. Variant chr3-129528801-C-A is described in Lovd as [Likely_pathogenic]. Variant chr3-129528801-C-A is described in Lovd as [Pathogenic]. Variant chr3-129528801-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461880Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 exome
AF:
AC:
1
AN:
1461880
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
727244
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2022 | Published functional studies demonstrate a damaging effect with impaired function and decreased thermal stability of the RHO protein as well as increased photoreceptor cell death (Noorwez et al., 2004; Comitato et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); 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: 19913029, 24853414, 21372525, 24515108, 19933196, 22110080, 24618321, 20164459, 21094163, 23185477, 8643442, 16799052, 29890221, 26427410, 34666717, 30977563, 18385078, 31717845, 20805032, 24214395, 22323724, 24106275, 21224384, 22276148, 27149983, 27654411, 26202387, 2137202, 28559085, 31100078, 31908405, 11139241, 2239971, 32037395, 14769795) - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 05, 2017 | The RHO c.68C>A; p.Pro23His variant (rs104893768) is published in the medical literature in individuals and families with autosomal dominant retinitis pigmentosa (RP; Bonilha 2015, Dryja 1990, Jacobson 2016). Additionally, other variants in this codon, p.Pro23Ala and p.Pro23Leu are described in individuals and families with autosomal dominant RP (Dryja 1991, Oh 2000). The c.68C>A; p.Pro23His variant is listed in the ClinVar database (Variation ID: 13013), but not in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at this position is well conserved across species and computational algorithms (PolyPhen-2, SIFT) predict the p.Pro23His variant is deleterious. Additionally, functional studies in a mouse model show this variant causes altered function (Comitato 2016). Considering available information, this variant is classified as pathogenic. Pathogenic RHO variants are causative for autosomal dominant or recessive retinitis pigmentosa (MIM#613731). References: Bonilha VL et al. Retinal histopathology in eyes from patients with autosomal dominant retinitis pigmentosa caused by rhodopsin mutations. Graefes Arch Clin Exp Ophthalmol. 2015 Dec;253(12):2161-9. Comitato A et al. Dominant and recessive mutations in rhodopsin activate different cell death pathways. Hum Mol Genet. 2016 Jul 1;25(13):2801-2812. Dryja TP et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature. 1990 Jan 25;343(6256):364-6. Dryja TP et al. Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9370-4. Jacobson SG et al. Complexity of the Class B Phenotype in Autosomal Dominant Retinitis Pigmentosa Due to Rhodopsin Mutations. Invest Ophthalmol Vis Sci. 2016 Sep 1;57(11):4847-4858. Oh KT et al. Description of a new mutation in rhodopsin, Pro23Ala, and comparison with electroretinographic and clinical characteristics of the Pro23His mutation. Arch Ophthalmol. 2000 Sep;118(9):1269-76. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 28, 2023 | This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 23 of the RHO protein (p.Pro23His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 1987956, 2137202, 11879142, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13013). 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 RHO protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RHO function (PMID: 1418997, 19913029, 22323724, 24853414). For these reasons, this variant has been classified as Pathogenic. - |
Retinitis pigmentosa 4 Pathogenic:2
| Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The RHO c.68C>A variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 14, 2005 | - - |
Pigmentary retinal dystrophy;C1864869:Congenital stationary night blindness autosomal dominant 1;C3151001:Retinitis pigmentosa 4 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 24, 2022 | - - |
RHO-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 25, 2024 | The RHO c.68C>A variant is predicted to result in the amino acid substitution p.Pro23His. This variant has been reported as a recurrent causative variant for autosomal dominant retinitis pigmentosa (see for examples Dryja et al. 1990. PubMed ID: 2137202; Sohocki et al. 2001. PubMed ID: 11139241; Coussa et al. 2019. PubMed ID: 31908405). Patients with this variant have been reported to exhibit interfamilial and intrafamilial phenotypic variability (Berson et al. 1991. PubMed ID: 1987956). Several functional studies have shown that the p.Pro23His substitution decreases both protein stability and activity (see for example Krebs et al. 2010. PubMed ID: 19913029). This variant has not been reported in the large population database gnomAD, indicating this variant is rare. Given the evidence, we interpret this variant as pathogenic for autosomal dominant disease. - |
Retinal dystrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 15, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of loop (P = 0.0435);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at