rs104893768

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.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. P23A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RHO
NM_000539.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.90

Publications

852 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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 19 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 chr3-129528800-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13055.Status of the report is no_assertion_criteria_provided, 0 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, 0.984

PP5

Variant 3-129528801-C-A is Pathogenic according to our data. Variant chr3-129528801-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000539.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHO	NM_000539.3	MANE Select	c.68C>A	p.Pro23His	missense	Exon 1 of 5	NP_000530.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHO	ENST00000296271.4	TSL:1 MANE Select	c.68C>A	p.Pro23His	missense	Exon 1 of 5	ENSP00000296271.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

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:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60394

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000681

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 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). 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%. 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.

Nov 21, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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)

Dec 05, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Retinitis pigmentosa 4

Pathogenic:2

Jan 14, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

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.

Pigmentary retinal dystrophy;C1864869:Congenital stationary night blindness autosomal dominant 1;C3151001:Retinitis pigmentosa 4

Pathogenic:1

Jan 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RHO-related disorder

Pathogenic:1

Sep 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Aug 15, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.7

PhyloP100

7.9

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.83

Gain of loop (P = 0.0435)

MVP

0.98

MPC

0.93

ClinPred

1.0

GERP RS

5.5

PromoterAI

0.040

Neutral

(source)

Varity_R

0.99

gMVP

0.92

Mutation Taster

=1/99

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over