rs104893792

chr3-129528884-G-Cchr3-129528884-G-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.151G>C(p.Gly51Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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. G51A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RHO NM_000539.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.68

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 hotspot region, there are 6 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 chr3-129528885-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 866399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 3-129528884-G-C is Pathogenic according to our data. Variant chr3-129528884-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129528884-G-C is described in Lovd as [Pathogenic]. Variant chr3-129528884-G-C is described in Lovd as [Pathogenic]. Variant chr3-129528884-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHO	NM_000539.3	c.151G>C	p.Gly51Arg	missense_variant	1/5	ENST00000296271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHO	ENST00000296271.4	c.151G>C	p.Gly51Arg	missense_variant	1/5	1	NM_000539.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 1994

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 13, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 51 of the RHO protein (p.Gly51Arg). 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: 8088850, 10967073, 28981474). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13047). 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: 19913029, 25096327). For these reasons, this variant has been classified as Pathogenic. -

RHO-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2023

The RHO c.151G>C variant is predicted to result in the amino acid substitution p.Gly51Arg. This variant has been reported in multiple individuals with autosomal dominant retinitis pigmentosa and in several of these reports was found to segregate with disease within a kindred (al-Maghtheh et al. 1993. PubMed ID: 8401533; Vaithinathan et al. 1994. PubMed ID: 8088850; Dryja and McGee. 2000. PubMed ID: 10967073; Comander et al. 2017. PubMed ID: 28981474). Functional studies have shown that the p.Gly51Arg substitution causes protein misfolding and mislocalization (Rakoczy et al. 2011. PubMed ID: 21094163; Wan. 2019. PubMed ID: 30977563). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.151G>C (p.Gly51Arg) as pathogenic for autosomal dominant disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.93		Gain of catalytic residue at G51 (P = 0.0373);
MVP		0.91
MPC		0.95
ClinPred		1.0	D
GERP RS		5.5
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: rs104893792; hg19: chr3-129247727;