chr3-129533704-G-T

Variant names:

• chr3-129533704-G-T
• rs104893795
• NM_000539.3:c.1033G>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000539.3(RHO):​c.1033G>T​(p.Val345Leu) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V345E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHO NM_000539.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.07
• Publications: 22 publications found

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]

RHO Gene-Disease associations (from GenCC):

• congenital stationary night blindness autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 4

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fundus albipunctatus

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS1: Transcript NM_000539.3 (RHO) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 13052
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 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 chr3-129533705-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 866976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 125 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.24182 (below the threshold of 3.09). Trascript score misZ: 1.4363 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital stationary night blindness, congenital stationary night blindness autosomal dominant 1, retinitis pigmentosa 4, fundus albipunctatus, retinitis pigmentosa.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 3-129533704-G-T is Pathogenic according to our data. Variant chr3-129533704-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 636081.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHO	NM_000539.3	c.1033G>T	p.Val345Leu	missense_variant	Exon 5 of 5	ENST00000296271.4	NP_000530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHO	ENST00000296271.4	c.1033G>T	p.Val345Leu	missense_variant	Exon 5 of 5	1	NM_000539.3	ENSP00000296271.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 345 of the RHO protein (p.Val345Leu). 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: 8045708, 8088850, 24938718; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 636081). 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 95%. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.59	P
Vest4		0.85
MutPred		0.76		Loss of catalytic residue at V345 (P = 0.0067);
MVP		0.90
MPC		0.36
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.87
gMVP		0.85
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893795; hg19: chr3-129252547;