chr3-129530918-G-T

Variant names:

• chr3-129530918-G-T
• rs104893774
• NM_000539.3:c.404G>T

Variant summary

Our verdict is Pathogenic. The variant received 27 ACMG points: 27P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000539.3(RHO):​c.404G>T​(p.Arg135Leu) 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. R135Q) has been classified as Uncertain significance.

• 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
• Publications: 50 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 27 ACMG points.

• PS1: Transcript NM_000539.3 (RHO) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 4 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 chr3-129530917-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13028.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, 0.995
• PP5: Variant 3-129530918-G-T is Pathogenic according to our data. Variant chr3-129530918-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHO	NM_000539.3	c.404G>T	p.Arg135Leu	missense_variant	Exon 2 of 5	ENST00000296271.4	NP_000530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHO	ENST00000296271.4	c.404G>T	p.Arg135Leu	missense_variant	Exon 2 of 5	1	NM_000539.3	ENSP00000296271.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000323 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 4 Pathogenic:2

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The RHO c.404G>T variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM1, PS3, PP1-S. Based on this evidence we have classified this variant as Pathogenic. -

Sep 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Sep 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 1484692, 29847639). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 135 of the RHO protein (p.Arg135Leu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 13024). 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. Experimental studies have shown that this missense change affects RHO function (PMID: 30977563). For these reasons, this variant has been classified as Pathogenic. -

Jul 14, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R135L (c.404 G>T) variant has been published previously in association with adRP (Andréasson et al., 1992; Fernandez-San et al., 2015). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R135L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position involved in rhodopsin kinase, transducin, and arrestin binding (Rakoczy et al., 2011) that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, functional studies have shown R135L leads to misfolding and impaired activity of the RHO protein (Chuang et al., 2004; Iannaccone et al., 2006). Missense variants in the same residue (R135G/W/P) and in nearby residues (L131PK, V137M, C140S) have been reported in the Human Gene Mutation Database in association with RP (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		10
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.97		Loss of helix (P = 0.1299);
MVP		0.99
MPC		0.97
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.99
Mutation Taster		=9/91	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: rs104893774; hg19: chr3-129249761;