3-129533711-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000539.3(RHO):c.1040C>T(p.Pro347Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,611,196 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P347A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000539.3 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RHO | NM_000539.3 | c.1040C>T | p.Pro347Leu | missense_variant | 5/5 | ENST00000296271.4 | NP_000530.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RHO | ENST00000296271.4 | c.1040C>T | p.Pro347Leu | missense_variant | 5/5 | 1 | NM_000539.3 | ENSP00000296271.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458968Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 725994
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74358
ClinVar
Submissions by phenotype
Retinitis pigmentosa 4 Pathogenic:5
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The RHO c.1040C>T 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: PM2, PM5, PS3, PP1-M. Based on this evidence we have classified this variant as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | Sep 01, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | RHO: PP1:Strong, PM1, PM2, PM5, PP4, PS4:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 347 of the RHO protein (p.Pro347Leu). This variant is present in population databases (rs29001566, gnomAD 0.0008%). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 2215617, 25221422). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13014). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2022 | Published functional studies demonstrate a damaging effect with partial delocalization of rhodopsin proteins to the lateral plasma membrane, Golgi apparatus, and synaptic terminal (Tam et al., 2000); Missense variants in the same residue (P347T, P347S, P347A, P347Q, P347R) reported in the Human Gene Mutation Database in individuals with retinitis pigmentosa (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9538889, 33629268, 32531858, 18385078, 34758253, 20555336, 25221422, 22217031, 18175313, 9335046, 2215617, 21094163, 26667666, 26202387, 28559085, 30972525, 30977563, 31054281, 31960602, 11139241, 32581362, 31630094, 33851411, 19074802, 31206141, 2021172, 33576794, 33090715, 33946315, 35656873, 11134067) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Retinal dystrophy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 15, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Retinitis pigmentosa Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel | Jul 24, 2023 | Clinical significance based on ACMG v2.0 - |
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Night blindness;C0241688:Peripheral visual field loss;C0344232:Blurred vision Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Microcephaly 17, primary, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
RHO-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 29, 2024 | The RHO c.1040C>T variant is predicted to result in the amino acid substitution p.Pro347Leu. This variant has been reported as causative for autosomal dominant retinitis pigmentosa (see for examples Dryja et al. 1990. PubMed ID: 2215617; Yang et al. 2014. PubMed ID: 25221422; Ge et al. 2015. PubMed ID: 26667666). Alternate substitutions of this amino acid (p.Pro347Ala, p.Pro347Gln. p.Pro347Thr, and p.Pro347Ser) have also been documented causative for retinitis pigmentosa, and in silico studies suggest that variants of the p.Pro347 residue affect cellular trafficking and protein interaction (Rakoczy et al. 2010. PubMed ID: 21094163). This variant is reported in 0.00077% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret this variant as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at