NM_000539.3(RHO):c.404G>T (p.Arg135Leu) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 26, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000256085.9

Allele description [Variation Report for NM_000539.3(RHO):c.404G>T (p.Arg135Leu)]

NM_000539.3(RHO):c.404G>T (p.Arg135Leu)

Gene:

RHO:rhodopsin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q22.1

Genomic location:

Preferred name:

NM_000539.3(RHO):c.404G>T (p.Arg135Leu)

HGVS:

NC_000003.12:g.129530918G>T
NG_009115.1:g.7280G>T
NM_000539.3:c.404G>TMANE SELECT
NP_000530.1:p.Arg135Leu
NC_000003.11:g.129249761G>T
P08100:p.Arg135Leu

Protein change:

R135L; ARG135LEU

Links:

UniProtKB: P08100#VAR_004796; OMIM: 180380.0011; dbSNP: rs104893774

NCBI 1000 Genomes Browser:

rs104893774

Molecular consequence:

NM_000539.3:c.404G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Mus musculus 14, 17 days embryo head cDNA, RIKEN full-length enriched library, c...
Mus musculus 14, 17 days embryo head cDNA, RIKEN full-length enriched library, clone:3230401I01 product:GLUTAMYL TRNA SYNTHETASE homolog [Homo sapiens], full insert sequence
gi|26380219|dbj|AK014324.2|

Nucleotide
PREDICTED: Mus musculus centrosomal protein 57 (Cep57), transcript variant X4, m...
PREDICTED: Mus musculus centrosomal protein 57 (Cep57), transcript variant X4, misc_RNA
gi|1907200827|ref|XR_001779042.3|

Nucleotide
Z0419
Z0419

biosample
Homologene neighbors for GEO Profiles (Select 112467023) (0)
GEO Profiles
Homologene neighbors for GEO Profiles (Select 65011404) (0)
GEO Profiles

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000322377	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jul 14, 2016)	germline	clinical testing	Citation Link,
SCV001590839	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 26, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 30977563, 1484692, 29847639, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000322377

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jul 14, 2016)

germline

clinical testing

Citation Link,

SCV001590839

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 26, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterizing variants of unknown significance in rhodopsin: A functional genomics approach.

Wan A, Place E, Pierce EA, Comander J.

Hum Mutat. 2019 Aug;40(8):1127-1144. doi: 10.1002/humu.23762. Epub 2019 Jun 22.

PubMed [citation]

PMID:: 30977563
PMCID:: PMC7027811

A six-generation family with autosomal dominant retinitis pigmentosa and a rhodopsin gene mutation (arginine-135-leucine).

Andréasson S, Ehinger B, Abrahamson M, Fex G.

Ophthalmic Paediatr Genet. 1992 Sep;13(3):145-53.

PubMed [citation]

PMID:: 1484692

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000322377.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The R135L (c.404 G>T) variant has been published previously in association with adRP (AndrÃ©asson 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001590839.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RHO function (PMID: 30977563). 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: 13024). 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 variant is not present in population databases (gnomAD no frequency). 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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