ClinVar Genomic variation as it relates to human health
NM_000321.3(RB1):c.59C>T (p.Pro20Leu)
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.
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.
Uncertain significance(3); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000321.3(RB1):c.59C>T (p.Pro20Leu)
Variation ID: 135115 Accession: VCV000135115.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q14.2 13: 48303971 (GRCh38) [ NCBI UCSC ] 13: 48878107 (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 Jun 9, 2014 Oct 8, 2024 Feb 5, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000321.3:c.59C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000312.2:p.Pro20Leu missense NC_000013.11:g.48303971C>T NC_000013.10:g.48878107C>T NG_009009.1:g.5225C>T LRG_517:g.5225C>T LRG_517t1:c.59C>T LRG_517p1:p.Pro20Leu - Protein change
- P20L
- Other names
- -
- Canonical SPDI
- NC_000013.11:48303970:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00011
The Genome Aggregation Database (gnomAD), exomes 0.00013
- Links
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 | ||
---|---|---|---|---|---|---|
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. |
|||
RB1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3631 | 3792 |
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. |
---|---|---|---|---|
Uncertain significance (2) |
criteria provided, single submitter
|
Apr 9, 2020 | RCV000121915.7 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Feb 5, 2024 | RCV000477348.18 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 24, 2022 | RCV000569325.5 | |
RB1-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Dec 31, 2023 | RCV003945101.2 |
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 benign
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Retinoblastoma
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000551840.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
|
|
Uncertain significance
(Apr 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967518.2
First in ClinVar: Aug 26, 2019 Last updated: Jul 03, 2020 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 2
|
|
Likely benign
(Jun 18, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002530857.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
|
|
Uncertain significance
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Retinoblastoma
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000838917.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
Uncertain Significance
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Retinoblastoma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004846298.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces proline with leucine at codon 20 of the RB1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces proline with leucine at codon 20 of the RB1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with retinoblastoma (PMID: 12541220, 14722923, 16343894, 29261756), but also in unaffected individuals (PMID: 16343894, 24728327, 29261756). This variant has been identified in 16/132530 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 43
|
|
Likely benign
(Oct 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000674710.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
Uncertain significance
(Dec 31, 2023)
|
no assertion criteria provided
Method: clinical testing
|
RB1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004757335.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The RB1 c.59C>T variant is predicted to result in the amino acid substitution p.Pro20Leu. This variant was reported in an individual with retinoblastoma (Parma et … (more)
The RB1 c.59C>T variant is predicted to result in the amino acid substitution p.Pro20Leu. This variant was reported in an individual with retinoblastoma (Parma et al. 2017. PubMed ID: 29261756, described as g.2118C>T), but was also found in the patient's asymptomatic mother and has been reported in a healthy ancestrally diverse cohort (Bodian et al. 2014. PubMed ID: 24728327, supplementary data). This variant was also described as a variant of uncertain significance in cohort of individuals with breast cancer (Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/135115/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000086120.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
RB1 gene mutations in Argentine retinoblastoma patients. Implications for genetic counseling. | Parma D | PloS one | 2017 | PMID: 29261756 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
Unilateral retinoblastoma, lack of familial history and older age does not exclude germline RB1 gene mutation. | Brichard B | European journal of cancer (Oxford, England : 1990) | 2006 | PMID: 16343894 |
Comprehensive screening for constitutional RB1 mutations by DHPLC and QMPSF. | Houdayer C | Human mutation | 2004 | PMID: 14722923 |
Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. | Richter S | American journal of human genetics | 2003 | PMID: 12541220 |
Text-mined citations for rs587778637 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.