3-129530917-C-T

Position:

• chr3-129530917-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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. R135G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RHO NM_000539.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 1.28

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 18 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 18) in uniprot entity OPSD_HUMAN there are 18 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, 0.994
• PP5: Variant 3-129530917-C-T is Pathogenic according to our data. Variant chr3-129530917-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129530917-C-T is described in Lovd as [Likely_pathogenic]. Variant chr3-129530917-C-T is described in Lovd as [Pathogenic]. Variant chr3-129530917-C-T is described in Lovd as [Pathogenic]. Variant chr3-129530917-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHO	NM_000539.3	c.403C>T	p.Arg135Trp	missense_variant	2/5	ENST00000296271.4	NP_000530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHO	ENST00000296271.4	c.403C>T	p.Arg135Trp	missense_variant	2/5	1	NM_000539.3	ENSP00000296271.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

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 Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa Pathogenic:4

Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Pathogenic, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
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 -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

Retinitis pigmentosa 4 Pathogenic:3

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	Apr 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. 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; 3Cnet: 0.74). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013028). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:18175313, 1862076, 25101269, 28559085). A different missense change at the same codon (p.Arg135Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013024, VCV000279882). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Retinal dystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -
Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 15, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	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). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2021	Published functional studies demonstrate a damaging effect; the variant results in the protein being retained in the ER leading to cellular apoptosis (Yu et al., 2019); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10521250, 1862076, 8841304, 18175313, 26962691, 25101269, 26794436, 21094163, 25619725, 8486634, 30635925, 29785639, 30977563, 31239368, 31054281, 31456290, 11139241, 32100970, 33576794, 1882937, 33090715, 25356976, 33781268, 33946315, 32037395, 28559085) -

Retinitis punctata albescens Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1997

- -

RHO-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2024

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	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.97		Loss of sheet (P = 0.3635);
MVP		0.99
MPC		0.88
ClinPred		1.0	D
GERP RS		2.0
Varity_R		0.99
gMVP		0.99

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: rs104893775; hg19: chr3-129249760; COSMIC: COSV56213571;