VCV000013014.44 - ClinVar

NM_000539.3(RHO):c.1040C>T (p.Pro347Leu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(16)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000539.3(RHO):c.1040C>T (p.Pro347Leu)

Variation ID: 13014 Accession: VCV000013014.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q22.1 3: 129533711 (GRCh38) [ NCBI UCSC ] 3: 129252554 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 11, 2015	Oct 20, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000539.3:c.1040C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000530.1:p.Pro347Leu	missense
NC_000003.12:g.129533711C>T
NC_000003.11:g.129252554C>T
NG_009115.1:g.10073C>T
	P08100:p.Pro347Leu

... more HGVS ... less HGVS

Protein change

P347L

Other names

NP_000530.1:p.(Pro347Leu)

Canonical SPDI

NC_000003.12:129533710:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA256662 UniProtKB: P08100#VAR_004834 OMIM: 180380.0002 dbSNP: rs29001566 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RHO		-	-	GRCh38 GRCh37	580	595

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Retinitis pigmentosa 4	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Apr 8, 2021	RCV000013888.24
Retinitis pigmentosa	Pathogenic (2)	criteria provided, single submitter	Jul 24, 2023	RCV000504743.5
Blurred vision Night blindness Peripheral visual field loss	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626702.4
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000490027.34
Retinal dystrophy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 1, 2023	RCV001075874.5
Microcephaly 17, primary, autosomal recessive	Pathogenic (1)	criteria provided, single submitter	Mar 26, 2024	RCV003989284.2
RHO-related disorder	Pathogenic (1)	no assertion criteria provided	May 29, 2024	RCV004755732.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Blurred vision Night blindness Peripheral visual field loss Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747405.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal unknown) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447284.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Rod-cone dystrophy (present) Sex: female
Pathogenic (Oct 01, 2023)	criteria provided, single submitter (Submitter's publication) Method: research	Retinal dystrophy Affected status: yes Allele origin: germline	Dept Of Ophthalmology, Nagoya University Accession: SCV004705682.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024
Pathogenic (Aug 15, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001241515.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Likely pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 4 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440597.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Pathogenic (Sep 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 4 Affected status: yes Allele origin: germline	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals Accession: SCV001443259.1 First in ClinVar: Nov 19, 2020 Last updated: Nov 19, 2020
Pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa 4 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573641.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (4) PubMed: 28041643‚ 25221422‚ 20555336‚ 2215617 Comment: The RHO c.1040C>T variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we … (more) The RHO c.1040C>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, PM5, PS3, PP1-M. Based on this evidence we have classified this variant as Pathogenic. (less)
Pathogenic (Oct 31, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577308.5 First in ClinVar: May 22, 2017 Last updated: Dec 17, 2022	Comment: Published functional studies demonstrate a damaging effect with partial delocalization of rhodopsin proteins to the lateral plasma membrane, Golgi apparatus, and synaptic terminal (Tam et … (more) Published functional studies demonstrate a damaging effect with partial delocalization of rhodopsin proteins to the lateral plasma membrane, Golgi apparatus, and synaptic terminal (Tam et al., 2000); Missense variants in the same residue (P347T, P347S, P347A, P347Q, P347R) reported in the Human Gene Mutation Database in individuals with retinitis pigmentosa (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9538889, 33629268, 32531858, 18385078, 34758253, 20555336, 25221422, 22217031, 18175313, 9335046, 2215617, 21094163, 26667666, 26202387, 28559085, 30972525, 30977563, 31054281, 31960602, 11139241, 32581362, 31630094, 33851411, 19074802, 31206141, 2021172, 33576794, 33090715, 33946315, 35656873, 11134067) (less)
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030290.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PP5, PM2, PM5, PM1, PS4, PP2.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 2 Sex: mixed Geographic origin: Portugal
Pathogenic (Jan 11, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001203323.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 2215617‚ 25221422 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 347 of the RHO protein (p.Pro347Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 347 of the RHO protein (p.Pro347Leu). This variant is present in population databases (rs29001566, gnomAD 0.0008%). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 2215617, 25221422). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13014). 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. (less)
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Microcephaly 17, primary, autosomal recessive Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004807351.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246343.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Comment: RHO: PP1:Strong, PM1, PM2, PM5, PP4, PS4:Supporting Number of individuals with the variant: 14
Pathogenic (Sep 01, 2010)	no assertion criteria provided Method: literature only	RETINITIS PIGMENTOSA 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034135.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015	Publications: PubMed (2) PubMed: 2215617‚ 20555336 Comment on evidence: In 8 of 28 unrelated patients with retinitis pigmentosa (see RP4; 613731), Dryja et al. (1990) found 2 heterozygous mutations involving C-to-T transitions at separate … (more) In 8 of 28 unrelated patients with retinitis pigmentosa (see RP4; 613731), Dryja et al. (1990) found 2 heterozygous mutations involving C-to-T transitions at separate nucleotides of codon 347 in the RHO gene. One was a change in the second position, from CCG to CTG, which resulted in substitution of leucine for proline (P347L). Also see 180380.0003. In a 5-generation Chinese Bai family segregating autosomal dominant RP, mapping to chromosome 3q, Guo et al. (2010) identified heterozygosity for the P347L mutation in the RHO gene. (less)
Pathogenic (May 29, 2024)	no assertion criteria provided Method: clinical testing	RHO-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005352129.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The RHO c.1040C>T variant is predicted to result in the amino acid substitution p.Pro347Leu. This variant has been reported as causative for autosomal dominant retinitis … (more) The RHO c.1040C>T variant is predicted to result in the amino acid substitution p.Pro347Leu. This variant has been reported as causative for autosomal dominant retinitis pigmentosa (see for examples Dryja et al. 1990. PubMed ID: 2215617; Yang et al. 2014. PubMed ID: 25221422; Ge et al. 2015. PubMed ID: 26667666). Alternate substitutions of this amino acid (p.Pro347Ala, p.Pro347Gln. p.Pro347Thr, and p.Pro347Ser) have also been documented causative for retinitis pigmentosa, and in silico studies suggest that variants of the p.Pro347 residue affect cellular trafficking and protein interaction (Rakoczy et al. 2010. PubMed ID: 21094163). This variant is reported in 0.00077% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret this variant as pathogenic. (less)
Likely pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598749.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 28041643‚ 2215617 Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European
Pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Retinitis pigmentosa 4 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760108.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
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Comment:

The RHO c.1040C>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, PM5, PS3, PP1-M. Based on this evidence we have classified this variant as Pathogenic.

Comment:

Published functional studies demonstrate a damaging effect with partial delocalization of rhodopsin proteins to the lateral plasma membrane, Golgi apparatus, and synaptic terminal (Tam et al., 2000); Missense variants in the same residue (P347T, P347S, P347A, P347Q, P347R) reported in the Human Gene Mutation Database in individuals with retinitis pigmentosa (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9538889, 33629268, 32531858, 18385078, 34758253, 20555336, 25221422, 22217031, 18175313, 9335046, 2215617, 21094163, 26667666, 26202387, 28559085, 30972525, 30977563, 31054281, 31960602, 11139241, 32581362, 31630094, 33851411, 19074802, 31206141, 2021172, 33576794, 33090715, 33946315, 35656873, 11134067)

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 347 of the RHO protein (p.Pro347Leu). This variant is present in population databases (rs29001566, gnomAD 0.0008%). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 2215617, 25221422). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13014). 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.

Comment:

The RHO c.1040C>T variant is predicted to result in the amino acid substitution p.Pro347Leu. This variant has been reported as causative for autosomal dominant retinitis pigmentosa (see for examples Dryja et al. 1990. PubMed ID: 2215617; Yang et al. 2014. PubMed ID: 25221422; Ge et al. 2015. PubMed ID: 26667666). Alternate substitutions of this amino acid (p.Pro347Ala, p.Pro347Gln. p.Pro347Thr, and p.Pro347Ser) have also been documented causative for retinitis pigmentosa, and in silico studies suggest that variants of the p.Pro347 residue affect cellular trafficking and protein interaction (Rakoczy et al. 2010. PubMed ID: 21094163). This variant is reported in 0.00077% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret this variant as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.	Peter VG	PNAS nexus	2023	PMID: 36909829
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.	Carss KJ	American journal of human genetics	2017	PMID: 28041643
Spectrum of rhodopsin gene mutations in Chinese patients with retinitis pigmentosa.	Yang G	Molecular vision	2014	PMID: 25221422
Linkage analysis and mutation screening of the rhodopsin gene in a Chinese Bai family with autosomal dominant retinitis pigmentosa.	Guo H	Journal of human genetics	2010	PMID: 20555336
Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa.	Dryja TP	The New England journal of medicine	1990	PMID: 2215617

Text-mined citations for rs29001566 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000539.3(RHO):c.1040C>T (p.Pro347Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs29001566 ...