VCV000013046.26 - ClinVar

NM_000539.3(RHO):c.448G>A (p.Glu150Lys)

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.

(6)

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.448G>A (p.Glu150Lys)

Variation ID: 13046 Accession: VCV000013046.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q22.1 3: 129530962 (GRCh38) [ NCBI UCSC ] 3: 129249805 (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 23, 2017	Nov 30, 2024	Oct 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000539.3:c.448G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000530.1:p.Glu150Lys	missense
NC_000003.12:g.129530962G>A
NC_000003.11:g.129249805G>A
NG_009115.1:g.7324G>A
	P08100:p.Glu150Lys

... more HGVS ... less HGVS

Protein change

E150K

Other names

NP_000530.1:p.(Glu150Lys)

Canonical SPDI

NC_000003.12:129530961:G:A

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

Component leading to Loss-of-Function (LoF); Functional Epilepsy Nomenclature for Ion Channels [ FENICS-0004]

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

1000 Genomes Project 30x 0.00016

Links

ClinGen: CA122824 UniProtKB: P08100#VAR_004799 OMIM: 180380.0033 dbSNP: rs104893791 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, autosomal recessive	Pathogenic (1)	no assertion criteria provided	Aug 4, 2006	RCV000013921.26
not provided	Pathogenic (1)	criteria provided, single submitter	Aug 15, 2023	RCV001045970.8
Retinitis pigmentosa 4	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 8, 2024	RCV001265186.2
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	May 27, 2024	RCV004794339.1
Autosomal recessive retinitis pigmentosa	Pathogenic (1)	no assertion criteria provided	Aug 22, 2022	RCV003105773.3

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 (Aug 15, 2023)	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: SCV001209847.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 23221340‚ 19960070‚ 26887858 Comment: Experimental studies have shown that this missense change affects RHO function (PMID: 23221340). For these reasons, this variant has been classified as Pathogenic. Advanced modeling … (more) Experimental studies have shown that this missense change affects RHO function (PMID: 23221340). For these reasons, this variant has been classified as Pathogenic. 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 not expected to disrupt RHO protein function. ClinVar contains an entry for this variant (Variation ID: 13046). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 150 of the RHO protein (p.Glu150Lys). This variant is present in population databases (rs104893791, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive retinitis pigmentosa (PMID: 19960070, 26887858). It has also been observed to segregate with disease in related individuals. (less)
Pathogenic (Oct 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 4 (Autosomal recessive inheritance) Affected status: no Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398880.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (4) PubMed: 19960070‚ 23221340‚ 26887858‚ 37165311 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital stationary night blindness (MIM#610445), retinitis pigmentosa 4 (MIM#613731) and retinitis punctata albescens (MIM#136880). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Variants associated with dominant conditions in this gene are known to have variable expressivity and age of onset (PMID: 26887858). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (12 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated 7 transmembrane receptor (rhodopsin family) domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been pathogenic or likely pathogenic by clinical laboratories in ClinVar, and has been observed as homozygous in four unrelated families in the literature all with retinitis pigmentosa (PMID: 19960070, 26887858, 37165311). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregates with disease in a large family retinitis pigmentosa (PMID: 19960070). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Knock-in mice homozygous for this variant displayed rapid retinal degeneration (PMID: 23221340). (SP) 1207 - Parental origin of the variant is unresolved (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Likely 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: SCV001443218.1 First in ClinVar: Nov 19, 2020 Last updated: Nov 19, 2020	Zygosity: Homozygote, Single Heterozygote
Pathogenic (May 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinal dystrophy Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV005415419.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 Comment: This variant was classified as Pathogenic based on ACMG criteria: PS3_sup, PM1_mod, PM2_mod, PP3_sup and PP2_sup	Publications: PubMed (2) PubMed: 7987385‚ 8317502 Number of individuals with the variant: 3 Sex: mixed Geographic origin: Pakistan;Khyber Pakhtunkhwa
Pathogenic (Aug 04, 2006)	no assertion criteria provided Method: literature only	RETINITIS PIGMENTOSA 4, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034168.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 23, 2024	Publications: PubMed (4) PubMed: 7987385‚ 8317502‚ 16737970‚ 26887858 Comment on evidence: In an Indian family in which 5 of 9 sibs, the offspring of unaffected first-cousin parents, had retinitis pigmentosa (RP4; 613731), Kumaramanickavel et al. (1994) … (more) In an Indian family in which 5 of 9 sibs, the offspring of unaffected first-cousin parents, had retinitis pigmentosa (RP4; 613731), Kumaramanickavel et al. (1994) found a G-to-A transition at codon 150 of the RHP gene, predicted to lead to a change from glutamate (GAG) to lysine (AAG) in the gene product. The 4 patients available for study were homozygous for the E150K mutation and 2 of the unaffected 4 sibs were heterozygous. (In the diagram of the pedigree, the order of the sibs was deliberately scrambled to disguise the identity of the heterozygotes.) Glu150 forms part of the second cytoplasmic loop of rhodopsin. Of the more than 60 RP-causing rhodopsin mutations identified, only one, cys140-to-ser, was located in the cytoplasmic loop (Macke et al., 1993). The E150K mutation in rhodopsin is located in its second cytoplasmic loop and is positioned at the rhodopsin dimer interface. Zhu et al. (2006) showed that neither global protein folding nor G-protein binding and activation by rhodopsin were significantly affected by the E150K mutation. However, E150K rhodopsin was aberrantly glycosylated and was retained in the cis/medial Golgi compartment. E150K rhodopsin did not alter plasma membrane targeting of wildtype rhodopsin in transfected HEK293 cells, and in the presence of excess wildtype rhodopsin, E150K rhodopsin was cotransported with wildtype rhodopsin through the trans-Golgi and delivered to the plasma membrane. In a Turkish brother and sister with an unusual RP phenotype, Van Schil et al. (2016) identified homozygosity for the E150K mutation in the RHO gene. In addition, the sibs were homozygous for 4 noncoding variants in the SAMD7 gene (620493) that showed reduced activity compared to wildtype SAMD7 in luciferase experiments and electroporation assays in retinal explants. Their unaffected mother and 2 unaffected sisters were heterozygous for the RHO and SAMD7 variants, as was a brother with minor subclinical manifestations. The authors suggested that the unusual nummular intraretinal pigment deposits observed in the affected sibs might be attributed to the SAMD7 variants, and postulated the presence of other modifying factors to account for the heterozygous brother's manifestations. (less)
Pathogenic (Aug 22, 2022)	no assertion criteria provided Method: research	Autosomal Recessive Retinitis Pigmentosa (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology Accession: SCV002600104.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Number of individuals with the variant: 9 Zygosity: Homozygote, Single Heterozygote Ethnicity/Population group: Pashtoon Geographic origin: Pakistan

Comment:

Experimental studies have shown that this missense change affects RHO function (PMID: 23221340). For these reasons, this variant has been classified as Pathogenic. 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 not expected to disrupt RHO protein function. ClinVar contains an entry for this variant (Variation ID: 13046). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 150 of the RHO protein (p.Glu150Lys). This variant is present in population databases (rs104893791, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive retinitis pigmentosa (PMID: 19960070, 26887858). It has also been observed to segregate with disease in related individuals.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital stationary night blindness (MIM#610445), retinitis pigmentosa 4 (MIM#613731) and retinitis punctata albescens (MIM#136880). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Variants associated with dominant conditions in this gene are known to have variable expressivity and age of onset (PMID: 26887858). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (12 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated 7 transmembrane receptor (rhodopsin family) domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been pathogenic or likely pathogenic by clinical laboratories in ClinVar, and has been observed as homozygous in four unrelated families in the literature all with retinitis pigmentosa (PMID: 19960070, 26887858, 37165311). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregates with disease in a large family retinitis pigmentosa (PMID: 19960070). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Knock-in mice homozygous for this variant displayed rapid retinal degeneration (PMID: 23221340). (SP) 1207 - Parental origin of the variant is unresolved (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Component leading to Loss-of-Function (LoF) (FENICS-0004)	Method not provided	Result not provided	Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology Accession: SCV002600104.2

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Unravelling the genetic basis of retinal dystrophies in Pakistani consanguineous families.	Marwan M	BMC ophthalmology	2023	PMID: 37165311
Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7.	Van Schil K	Scientific reports	2016	PMID: 26887858
Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization.	Zhang N	The Journal of clinical investigation	2013	PMID: 23221340
A homozygous p.Glu150Lys mutation in the opsin gene of two Pakistani families with autosomal recessive retinitis pigmentosa.	Azam M	Molecular vision	2009	PMID: 19960070
Autosomal recessive retinitis pigmentosa and E150K mutation in the opsin gene.	Zhu L	The Journal of biological chemistry	2006	PMID: 16737970
Missense rhodopsin mutation in a family with recessive RP.	Kumaramanickavel G	Nature genetics	1994	PMID: 7987385
Identification of novel rhodopsin mutations responsible for retinitis pigmentosa: implications for the structure and function of rhodopsin.	Macke JP	American journal of human genetics	1993	PMID: 8317502

Text-mined citations for rs104893791 ...

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 Dec 22, 2024

ClinVar Genomic variation as it relates to human health

NM_000539.3(RHO):c.448G>A (p.Glu150Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104893791 ...