rs104893772

chr3-129528999-G-Achr3-129528999-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000539.3(RHO):c.266G>A(p.Gly89Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G89R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RHO NM_000539.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.78

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr3-129528998-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 636083.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 3-129528999-G-A is Pathogenic according to our data. Variant chr3-129528999-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129528999-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-129528999-G-A is described in Lovd as [Pathogenic]. Variant chr3-129528999-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHO	NM_000539.3	c.266G>A	p.Gly89Asp	missense_variant	1/5	ENST00000296271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHO	ENST00000296271.4	c.266G>A	p.Gly89Asp	missense_variant	1/5	1	NM_000539.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Sep 01, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1991	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	RHO: PP1:Strong, PM1, PM2, PS4:Moderate, PM5:Supporting, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 89 of the RHO protein (p.Gly89Asp). 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: 1833777, 1862076, 10967073). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13021). 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 80%. Experimental studies have shown that this missense change affects RHO function (PMID: 1924344, 12660238, 21352497). For these reasons, this variant has been classified as Pathogenic. -

Pigmentary retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

The c.266G>A;p.(Gly89Asp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:13021; PMID: 1833777; 1862076; 1924344; 10967073; 12660238; 21352497) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 1924344; 12660238; 21352497) - PS3_moderate. This variant is not present in population databases (rs104893772, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 1833777) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.18	T
Polyphen		0.78	P
Vest4		0.95
MutPred		0.76		Loss of glycosylation at S93 (P = 0.0272);
MVP		0.97
MPC		0.64
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.97

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

Other links and lift over

dbSNP: rs104893772; hg19: chr3-129247842;