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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RHO
NM_000539.3 missense

Scores

9
8
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 5.47
Variant links:
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 16 ACMG points.

PM1
In a region_of_interest Interaction with SAG (size 18) in uniprot entity OPSD_HUMAN there are 32 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, 0.925
PP5
Variant 3-129533711-C-T is Pathogenic according to our data. Variant chr3-129533711-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129533711-C-T is described in Lovd as [Pathogenic]. Variant chr3-129533711-C-T is described in Lovd as [Likely_pathogenic]. Variant chr3-129533711-C-T is described in Lovd as [Likely_pathogenic]. Variant chr3-129533711-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RHONM_000539.3 linkuse as main transcriptc.1040C>T p.Pro347Leu missense_variant 5/5 ENST00000296271.4 NP_000530.1 P08100

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RHOENST00000296271.4 linkuse as main transcriptc.1040C>T p.Pro347Leu missense_variant 5/51 NM_000539.3 ENSP00000296271.3 P08100

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1458968
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
725994
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152228
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinitis pigmentosa 4 Pathogenic:5
Pathogenic, criteria provided, single submitterresearchOcular Genomics Institute, Massachusetts Eye and EarApr 08, 2021The 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 providedliterature onlyOMIMSep 01, 2010- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Genomic Medicine, Manchester, Central Manchester University HospitalsSep 01, 2020- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Pathogenic, no assertion criteria providedclinical testingGenomics England Pilot Project, Genomics England-- -
not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024RHO: PP1:Strong, PM1, PM2, PM5, PP4, PS4:Supporting -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2024This 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 submitterclinical testingGeneDxOct 31, 2022Published 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 submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Retinal dystrophy Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsAug 15, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2022- -
Pathogenic, criteria provided, single submitterresearchDept Of Ophthalmology, Nagoya UniversityOct 01, 2023- -
Retinitis pigmentosa Pathogenic:2
Pathogenic, criteria provided, single submitterresearchOphthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology BaselJul 24, 2023Clinical significance based on ACMG v2.0 -
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
Night blindness;C0241688:Peripheral visual field loss;C0344232:Blurred vision Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -
Microcephaly 17, primary, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 26, 2024- -
RHO-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 29, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.92
D
MetaSVM
Uncertain
-0.048
T
MutationAssessor
Uncertain
2.0
M
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.2
D
REVEL
Uncertain
0.62
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.83
MutPred
0.76
Gain of stability (P = 0.0462);
MVP
0.91
MPC
0.85
ClinPred
0.94
D
GERP RS
5.4
Varity_R
0.59
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs29001566; hg19: chr3-129252554; COSMIC: COSV99960837; API