NM_000539.3(RHO):c.800C>T (p.Pro267Leu) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 22, 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:: RCV001582479.9

Allele description [Variation Report for NM_000539.3(RHO):c.800C>T (p.Pro267Leu)]

NM_000539.3(RHO):c.800C>T (p.Pro267Leu)

Gene:

RHO:rhodopsin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q22.1

Genomic location:

Preferred name:

NM_000539.3(RHO):c.800C>T (p.Pro267Leu)

HGVS:

NC_000003.12:g.129532636C>T
NG_009115.1:g.8998C>T
NM_000539.3:c.800C>TMANE SELECT
NP_000530.1:p.Pro267Leu
NC_000003.11:g.129251479C>T
P08100:p.Pro267Leu

Protein change:

P267L; PRO267LEU

Links:

UniProtKB: P08100#VAR_004825; OMIM: 180380.0022; dbSNP: rs104893781

NCBI 1000 Genomes Browser:

rs104893781

Molecular consequence:

NM_000539.3:c.800C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001820260	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 30, 2019)	germline	clinical testing	Citation Link,
SCV002246500	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 22, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29890221, 1897520, 26962691, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001820260

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 30, 2019)

germline

clinical testing

Citation Link,

SCV002246500

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 22, 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

Misfolded rhodopsin mutants display variable aggregation properties.

Gragg M, Park PS.

Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):2938-2948. doi: 10.1016/j.bbadis.2018.06.004. Epub 2018 Jun 8.

PubMed [citation]

PMID:: 29890221
PMCID:: PMC6066411

Identification of novel rhodopsin mutations associated with retinitis pigmentosa by GC-clamped denaturing gradient gel electrophoresis.

Sheffield VC, Fishman GA, Beck JS, Kimura AE, Stone EM.

Am J Hum Genet. 1991 Oct;49(4):699-706.

PubMed [citation]

PMID:: 1897520
PMCID:: PMC1683182

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV001820260.1

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

Description

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)

#	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, SCV002246500.3

#	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. 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).

#	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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