3-129530917-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000539.3(RHO):c.403C>T(p.Arg135Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 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. R135Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RHO
NM_000539.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 1.28

Publications

62 publications found

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]

RHO Gene-Disease associations (from GenCC):

congenital stationary night blindness autosomal dominant 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 4
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
congenital stationary night blindness
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
fundus albipunctatus
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

RHO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 chr3-129530918-GG-TT is described in ClinVar as Pathogenic. ClinVar VariationId is 279882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 125 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.24182 (below the threshold of 3.09). Trascript score misZ: 1.4363 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital stationary night blindness, congenital stationary night blindness autosomal dominant 1, retinitis pigmentosa 4, fundus albipunctatus, retinitis pigmentosa.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 3-129530917-C-T is Pathogenic according to our data. Variant chr3-129530917-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHO	NM_000539.3 link	c.403C>T	p.Arg135Trp	missense_variant	Exon 2 of 5	ENST00000296271.4	NP_000530.1	P08100

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHO	ENST00000296271.4 link	c.403C>T	p.Arg135Trp	missense_variant	Exon 2 of 5	1	NM_000539.3	ENSP00000296271.3		P08100

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 4

Pathogenic:4

Jan 11, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.93 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013028 /PMID: 1862076 /3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 18175313, 1862076, 25101269, 28559085). Different missense changes at the same codon (p.Arg135Gly, p.Arg135Leu, p.Arg135Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013024, VCV000279882, VCV001455410, VCV001456261 /PMID: 1484692, 1862076, 8406457). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 12, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2020

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa

Pathogenic:4

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jul 24, 2023

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Clinical significance based on ACMG v2.0 -

not provided

Pathogenic:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 135 of the RHO protein (p.Arg135Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 1862076, 18175313, 25101269, 28559085). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13028). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Jul 22, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect as the variant results in the protein being retained in the ER leading to cellular apoptosis (PMID: 30635925); 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: 10521250, 31429209, 32531858, 18385078, 1862076, 8841304, 18175313, 26962691, 25101269, 26794436, 21094163, 25619725, 8486634, 30635925, 29785639, 30977563, 31239368, 31054281, 31456290, 11139241, 32100970, 33576794, 1882937, 33090715, 25356976, 33781268, 33946315, 32037395, 34919893, 34448047, 37712069, 33057194, 36460718, 31213501, 36729443, 36819107, 36909829, 37217489, 36284460, 34321860, 35982159, 28559085, 38219857, 38479725) -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RHO: PP1:Strong, PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PS3:Supporting -

Retinal dystrophy

Pathogenic:3

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Retinitis punctata albescens

Pathogenic:1

Apr 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

RHO-related disorder

Pathogenic:1

Aug 21, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RHO c.403C>T variant is predicted to result in the amino acid substitution p.Arg135Trp. This variant has been reported in individuals with autosomal dominant retinitis pigmentosa (see for examples Sung et al. 1991. PubMed ID: 1862076; Beryozkin et al. 2016. PubMed ID: 26962691). Additionally, different substitutions of the same amino acid (p.Arg135Gly, p.Arg135Leu) have been reported in individuals with for retinitis pigmentosa (Bunge et al. 1993. PubMed ID: 8406457; Andreasson et al. 1992. PubMed ID: 1484692). In silico studies suggest that the substitution of the p.Arg135 codon affects endocytosis and protein interaction (Mokarzel-Falcón et al. 2008. PubMed ID: 18175313; Rakoczy et al. 2011, PubMed ID: 21094163). Given all the evidence, we interpret c.403C>T (p.Arg135Trp) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

PhyloP100

1.3

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.97

Loss of sheet (P = 0.3635);

MVP

0.99

MPC

0.88

ClinPred

1.0

GERP RS

2.0

Varity_R

0.99

gMVP

0.99

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over