rs104893781

Positions:

• chr3-129532636-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.800C>T​(p.Pro267Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 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. P267R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RHO NM_000539.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.17

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 helix (size 36) in uniprot entity OPSD_HUMAN there are 13 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, 0.993
• PP5: Variant 3-129532636-C-T is Pathogenic according to our data. Variant chr3-129532636-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129532636-C-T is described in Lovd as [Likely_pathogenic]. Variant chr3-129532636-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.800C>T	p.Pro267Leu	missense_variant	4/5	ENST00000296271.4	NP_000530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHO	ENST00000296271.4	c.800C>T	p.Pro267Leu	missense_variant	4/5	1	NM_000539.3	ENSP00000296271	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 4 Pathogenic:2

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

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2019	Published functional studies demonstrate a damaging effect with decreased regeneration of 11-cis-retinal and accumulation in the endoplasmic reticulum (Sung et al., 1993); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31456290, 30977563, 9228242, 1444916, 16799052, 17936999, 26962691, 1897520, 21785698, 8193125, 9380676, 26872967, 15563868, 1358680, 8253795, 28966884, 10409707, 21094163, 29890221) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro267 amino acid residue in RHO. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RHO function (PMID: 29890221). 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. ClinVar contains an entry for this variant (Variation ID: 13034). This missense change has been observed in individuals with autosomal dominant inherited retinal dystrophy (PMID: 1897520, 26962691). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 267 of the RHO protein (p.Pro267Leu). -

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	0.97
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.95		Loss of sheet (P = 0.1158);
MVP		0.98
MPC		0.87
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104893781; hg19: chr3-129251479;