VCV000002193.55 - ClinVar

NM_178857.6(RP1L1):c.133C>T (p.Arg45Trp)

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.

(14)

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.

Conflicting classifications of pathogenicity
Pathogenic(4); Likely pathogenic(4); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_178857.6(RP1L1):c.133C>T (p.Arg45Trp)

Variation ID: 2193 Accession: VCV000002193.55

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p23.1 8: 10623069 (GRCh38) [ NCBI UCSC ] 8: 10480579 (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	May 19, 2013	Oct 20, 2024	Apr 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_178857.6:c.133C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_849188.4:p.Arg45Trp	missense
NC_000008.11:g.10623069G>A
NC_000008.10:g.10480579G>A
NG_028035.1:g.37039C>T

Protein change

R45W

Other names

Canonical SPDI

NC_000008.11:10623068:G:A

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.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA115397 OMIM: 608581.0001 dbSNP: rs267607017 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.
RP1L1		-	-	GRCh38 GRCh38 GRCh37	1342	1471

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.
Occult macular dystrophy	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Nov 18, 2021	RCV000002277.21
not provided	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Apr 1, 2024	RCV000726920.38
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jul 30, 2019	RCV001074376.3
Retinitis pigmentosa 88	Pathogenic (1)	criteria provided, single submitter	Dec 3, 2019	RCV001197672.3

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.
Likely pathogenic (Dec 21, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000704172.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 15, 2018	Publications: PubMed (6) PubMed: 20826268‚ 23281133‚ 23619761‚ 23745001‚ 25908487‚ 26782618 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RP1L1 Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Jul 30, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239954.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Likely pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447606.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Occult macular dystrophy (present) Sex: male
Pathogenic (Dec 03, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 88 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368451.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP1-S,PP3.
Likely pathogenic (Nov 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Occult macular dystrophy Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580293.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4, PM2_SUP, PP1, PP3, BS4	Number of individuals with the variant: 1 Sex: female
Pathogenic (Jan 02, 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: SCV001585398.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 20826268‚ 30025130 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 45 of the RP1L1 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 45 of the RP1L1 protein (p.Arg45Trp). This variant is present in population databases (rs267607017, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant occult macular dystrophy (PMID: 20826268, 30025130). It has also been observed to segregate with disease in related individuals. This variant is also known as c.362C>T. ClinVar contains an entry for this variant (Variation ID: 2193). 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 RP1L1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain significance (Aug 22, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Occult macular dystrophy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000916218.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (6) PubMed: 26782618‚ 20826268‚ 27623337‚ 23619761‚ 23281133‚ 22504327 Comment: The RP1L1 c.133C>T (p.Arg45Trp) missense variant has been reported in at least six studies and is found in a heterozygous state in a total of … (more) The RP1L1 c.133C>T (p.Arg45Trp) missense variant has been reported in at least six studies and is found in a heterozygous state in a total of 35 individuals with occult macular dystrophy, including 15 unrelated individuals. The variant is also found in 13 unaffected family members (Akahori et al. 2010; Okuno et al. 2013; Hayashi et al. 2012; Davidson et al. 2013; Piermarocchi et al. 2016; Fujinami al. 2016). Due to the presence of both affected and unaffected family members carrying the p.Arg45Trp variant in a heterozygous state, Akahori et al. (2010) and Davidson et al. (2013) suggest that the variant may exhibit reduced penetrance or later age of onset in asymptomatic carriers. The p.Arg45Trp variant was absent from 976 controls but is reported at a frequency of 0.000025 in the total population of the Genome Aggregation Database. Based on the evidence, the p.Arg45Trp variant is classified a variant of unknown significance but suspicious for pathogenicity for occult macular dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Apr 01, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001770569.4 First in ClinVar: Aug 07, 2021 Last updated: Sep 29, 2024	Comment: Reduced penetrance has been reported for the p.(R45W) variant (PMID: 30025130); In silico analysis supports that this missense variant has a deleterious effect on protein … (more) Reduced penetrance has been reported for the p.(R45W) variant (PMID: 30025130); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23281133, 34440443, 32458067, 25908487, 23619761, 26782618, 22466457, 29555955, 28890726, 27579568, 35464678, 32360662, 32176261, 22504327, 23745001, 27623337, 28195981, 31028767, 31193770, 32940107, 37510321, 36460718, 36729443, 37217489, 32531858, 20826268, 30025130) (less)
Likely pathogenic (Oct 01, 2023)	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: SCV001245752.24 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: RP1L1: PP1:Strong, PS4:Moderate, PM2:Supporting Number of individuals with the variant: 20
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975316.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
risk factor (Mar 01, 2013)	no assertion criteria provided Method: literature only	OCCULT MACULAR DYSTROPHY, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022435.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 29, 2020	Publications: PubMed (3) PubMed: 20826268‚ 23281133‚ 30025130 Comment on evidence: In affected members of 3 Japanese families with occult macular dystrophy (OCMD; 613587), Akahori et al. (2010) identified heterozygosity for a 362C-T transition in the … (more) In affected members of 3 Japanese families with occult macular dystrophy (OCMD; 613587), Akahori et al. (2010) identified heterozygosity for a 362C-T transition in the RP1L1 gene, resulting in an arg45-to-trp (R45W) substitution. The mutation was not found in 876 Japanese controls. Akahori et al. (2010) noted that 3 apparently unaffected individuals from 2 families carried the R45W mutation, suggesting either reduced penetrance of the mutation or possibly a later onset of disease for these individuals. Davidson et al. (2013) identified heterozygosity for the R45W variant in 5 of 28 OCMD probands; however, the variant was also detected in 8 asymptomatic carriers, including 3 who were over 55 years of age and showed no signs of OCMD on examination as well as a 90-year-old woman, for a penetrance of only 38%. Davidson et al. (2013) concluded that the R45W variant represents a risk factor for OCMD rather than a causative mutation. From a cohort of 42 patients with OCMD from 27 mostly German families, Zobor et al. (2018) identified 39 individuals in 25 families who were heterozygous for the R45W mutation in the RP1L1 gene. Segregation analysis revealed 9 R45W unaffected mutation carriers or obligate carriers in 5 families, confirming reduced penetrance, which was calculated to be 82.7% in this cohort. However, the authors noted that most of the asymptomatic mutation carriers were not clinically investigated and might have shown subclinical signs of disease. In addition, age of onset varied from 6 years to 74 years of age, suggesting that variable expressivity might contribute to the apparent reduced penetrance. All patients showed characteristic functional and morphologic findings for OCMD in both eyes, including 1 patient who was homozygous for the R45W variant, whose parents were both asymptomatic carriers. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001922196.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955747.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely pathogenic (Aug 26, 2021)	no assertion criteria provided Method: clinical testing	Occult macular dystrophy Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002011783.1 First in ClinVar: Nov 05, 2021 Last updated: Nov 05, 2021
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Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 45 of the RP1L1 protein (p.Arg45Trp). This variant is present in population databases (rs267607017, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant occult macular dystrophy (PMID: 20826268, 30025130). It has also been observed to segregate with disease in related individuals. This variant is also known as c.362C>T. ClinVar contains an entry for this variant (Variation ID: 2193). 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 RP1L1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Comment:

The RP1L1 c.133C>T (p.Arg45Trp) missense variant has been reported in at least six studies and is found in a heterozygous state in a total of 35 individuals with occult macular dystrophy, including 15 unrelated individuals. The variant is also found in 13 unaffected family members (Akahori et al. 2010; Okuno et al. 2013; Hayashi et al. 2012; Davidson et al. 2013; Piermarocchi et al. 2016; Fujinami al. 2016). Due to the presence of both affected and unaffected family members carrying the p.Arg45Trp variant in a heterozygous state, Akahori et al. (2010) and Davidson et al. (2013) suggest that the variant may exhibit reduced penetrance or later age of onset in asymptomatic carriers. The p.Arg45Trp variant was absent from 976 controls but is reported at a frequency of 0.000025 in the total population of the Genome Aggregation Database. Based on the evidence, the p.Arg45Trp variant is classified a variant of unknown significance but suspicious for pathogenicity for occult macular dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

Reduced penetrance has been reported for the p.(R45W) variant (PMID: 30025130); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23281133, 34440443, 32458067, 25908487, 23619761, 26782618, 22466457, 29555955, 28890726, 27579568, 35464678, 32360662, 32176261, 22504327, 23745001, 27623337, 28195981, 31028767, 31193770, 32940107, 37510321, 36460718, 36729443, 37217489, 32531858, 20826268, 30025130)

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
Phenotype Variations Caused by Mutations in the RP1L1 Gene in a Large Mainly German Cohort.	Zobor D	Investigative ophthalmology & visual science	2018	PMID: 30025130
Novel RP1L1 Variants and Genotype-Photoreceptor Microstructural Phenotype Associations in Cohort of Japanese Patients With Occult Macular Dystrophy.	Fujinami K	Investigative ophthalmology & visual science	2016	PMID: 27623337
Occult macular dystrophy in an Italian family carrying a mutation in the RP1L1 gene.	Piermarocchi S	Molecular medicine reports	2016	PMID: 26782618
Multimodal Approach to Monitoring and Investigating Cone Structure and Function in an Inherited Macular Dystrophy.	Ziccardi L	American journal of ophthalmology	2015	PMID: 25908487
Clinical and genetic characteristics of Korean occult macular dystrophy patients.	Ahn SJ	Investigative ophthalmology & visual science	2013	PMID: 23745001
Elderly case of pseudo-unilateral occult macular dystrophy with Arg45Trp mutation in RP1L1 gene.	Okuno T	Documenta ophthalmologica. Advances in ophthalmology	2013	PMID: 23619761
RP1L1 variants are associated with a spectrum of inherited retinal diseases including retinitis pigmentosa and occult macular dystrophy.	Davidson AE	Human mutation	2013	PMID: 23281133
Autosomal dominant occult macular dystrophy with an RP1L1 mutation (R45W).	Hayashi T	Optometry and vision science : official publication of the American Academy of Optometry	2012	PMID: 22504327
Dominant mutations in RP1L1 are responsible for occult macular dystrophy.	Akahori M	American journal of human genetics	2010	PMID: 20826268
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RP1L1	-	-	-	-

Text-mined citations for rs267607017 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_178857.6(RP1L1):c.133C>T (p.Arg45Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267607017 ...