rs104893787

Positions:

• chr3-129529062-G-A

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.329G>A​(p.Cys110Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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. C110F) 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:4
• Conservation: PhyloP100: 10.0

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 disulfide_bond (size 77) in uniprot entity OPSD_HUMAN there are 119 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, 0.995
• PP5: Variant 3-129529062-G-A is Pathogenic according to our data. Variant chr3-129529062-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129529062-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-129529062-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHO	NM_000539.3	c.329G>A	p.Cys110Tyr	missense_variant	1/5	ENST00000296271.4	NP_000530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHO	ENST00000296271.4	c.329G>A	p.Cys110Tyr	missense_variant	1/5	1	NM_000539.3	ENSP00000296271.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2020	Published functional studies demonstrate a damaging effect with disruption of disulfide bonds resulting in severe protein misfolding and inability to bind 11-cis retinal and form mature rhodopsin (Krebs et al., 2010; Behnen et al., 2018); Identified in individuals with autosomal dominant retinitis pigmentosa referred for genetic testing at GeneDx and in published literature (Dryja et al., 1992; Vaithinathan et al., 1994; Milla et al., 1998); Categorized as a Class 2 RHO variant, characterized by misfolding, ER retention, and instability, in published literature (Athanasiou et al., 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants at the same residue and in nearby residues reported in the Human Gene Mutation Database in individuals with retinitis pigmentosa (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 33576794, 30977563, 29042326, 8088850, 8401533, 9810568, 10051572, 19136713, 30240733, 19913029, 21094163, 16332273, 29773803, 1358680) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2020	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect RHO protein function (PMID: 19913029, 30240733). This variant has been observed to segregate with autosomal dominant retinitis pigmentosa in families (PMID: 8088850, 9810568). ClinVar contains an entry for this variant (Variation ID: 13035). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 110 of the RHO protein (p.Cys110Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. -

Retinitis pigmentosa 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 1994

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	4.7	H
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.94		Loss of glycosylation at T108 (P = 0.1174);
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
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: rs104893787; hg19: chr3-129247905;