This sequence change replaces cysteine with arginine at codon 712 of the RB1 protein (p.Cys712Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with retinoblastoma and has been observed to segregate with retinoblastoma in a family (PMID: 9671401, 10671068, 11668642, 22084214). It has also been reported to be associated with a reduced penetrant phenotype in the literature (PMID: 16269091, 12541220, 10617920). ClinVar contains an entry for this variant (Variation ID: 13092). This variant has been reported to affect RB1 protein function in vitro (PMID: 18677112, 10486322). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Pathogenic/Likely pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 3 (Most recent: Nov 30, 2020)
- Last evaluated:
- Mar 28, 2019
- Accession:
- VCV000013092.4
- Variation ID:
- 13092
- Description:
- single nucleotide variant
Help
NM_000321.2(RB1):c.2134T>C (p.Cys712Arg)
- Allele ID
- 28131
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 13q14.2
- Genomic location
- 13: 48463758 (GRCh38) GRCh38 UCSC
- 13: 49037894 (GRCh37) GRCh37 UCSC
- HGVS
-
Nucleotide Protein Molecular
consequenceNC_000013.10:g.49037894T>C NC_000013.11:g.48463758T>C NM_000321.2:c.2134T>C NP_000312.2:p.Cys712Arg missense LRG_517t1:c.2134T>C LRG_517p1:p.Cys712Arg NG_009009.1:g.165012T>C LRG_517:g.165012T>C P06400:p.Cys712Arg - Protein change
- C712R
- Other names
- -
- Canonical SPDI
- NC_000013.11:48463757:T:C
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- ClinGen: CA026423
- UniProtKB: P06400#VAR_005587
- OMIM: 614041.0024
- dbSNP: rs137853296
Help
Aggregate interpretations per condition
Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
---|---|---|---|---|---|
Pathogenic | 2 | criteria provided, single submitter | Mar 28, 2019 | RCV000013968.3 | |
Likely pathogenic | 1 | criteria provided, single submitter | Mar 9, 2018 | RCV000492516.2 |
Help
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation | Variation viewer | Related variants | ||
---|---|---|---|---|---|---|
HI score Help | TS score Help | Within gene | All | |||
RB1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1114 | 1199 |
Submitted interpretations and evidence
HelpInterpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | Supporting information
(See all) |
---|---|---|---|---|
Pathogenic
(Mar 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinoblastoma
Allele origin:
germline
|
Invitae
Accession: SCV001224741.1
Submitted: (Feb 06, 2020) |
Comment:
This sequence change replaces cysteine with arginine at codon 712 of the RB1 protein (p.Cys712Arg). The cysteine residue is highly conserved and there is a … (more)
This sequence change replaces cysteine with arginine at codon 712 of the RB1 protein (p.Cys712Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with retinoblastoma and has been observed to segregate with retinoblastoma in a family (PMID: 9671401, 10671068, 11668642, 22084214). It has also been reported to be associated with a reduced penetrant phenotype in the literature (PMID: 16269091, 12541220, 10617920). ClinVar contains an entry for this variant (Variation ID: 13092). This variant has been reported to affect RB1 protein function in vitro (PMID: 18677112, 10486322). For these reasons, this variant has been classified as Pathogenic. (less)
|
Likely pathogenic
(Mar 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000580826.4
Submitted: (Nov 30, 2020) |
Comment:
The p.C712R variant (also known as c.2134T>C), located in coding exon 21 of the RB1 gene, results from a T to C substitution at nucleotide … (more)
The p.C712R variant (also known as c.2134T>C), located in coding exon 21 of the RB1 gene, results from a T to C substitution at nucleotide position 2134. The cysteine at codon 712 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported to be associated with a low penetrant phenotype since it has been identified in multiple families with cases of unilateral or regressed tumors and/or unaffected individuals considered at risk for retinoblastoma (Cowell J et al Oncogene. 1998 Jun 18;16(24):3211-3; Valverde J et al BMC Genet. 2005 Nov 4;6:53; Richter S et al Am J Hum Genet. 2003 Feb;72(2):253-69). This variant is located in the A/B pocket and intervening spacer region of the RB1 protein, a critical region of RB1 (Richter S et al Am J Hum Genet. 2003 Feb;72(2):253-69). While alterations to a critical region of the gene are often deleterious, the temperature-sensitive pocket activity of the RB1 gene may explain the observed low penetrance of the C712R alteration (Valverde J et al BMC Genet. 2005 Nov 4;6:53). This amino acid position is highly conserved in available vertebrate species. This splice prediction software does not predict a deleterious effect on splicing. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
Pathogenic
(Oct 01, 1999)
|
no assertion criteria provided
Method: literature only
|
RETINOBLASTOMA
Allele origin:
germline
|
OMIM
Accession: SCV000034215.1
Submitted: (Dec 30, 2010) |
|
Functional evidence
HelpThere 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 this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Outcomes of integrating genetics in management of patients with retinoblastoma. | Dhar SU | Archives of ophthalmology (Chicago, Ill. : 1960) | 2011 | PMID: 22084214 |
Low-penetrant RB allele in small-cell cancer shows geldanamycin instability and discordant expression with mutant ras. | Park Y | Cell cycle (Georgetown, Tex.) | 2008 | PMID: 18677112 |
RB1 gene mutation up-date, a meta-analysis based on 932 reported mutations available in a searchable database. | Valverde JR | BMC genetics | 2005 | PMID: 16269091 |
Sensitive multistep clinical molecular screening of 180 unrelated individuals with retinoblastoma detects 36 novel mutations in the RB1 gene. | Nichols KE | Human mutation | 2005 | PMID: 15884040 |
Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. | Richter S | American journal of human genetics | 2003 | PMID: 12541220 |
Novel RB1 gene constitutional mutations found in Polish patients with familial and/or bilateral retinoblastoma. | Jakubowska A | Human mutation | 2001 | PMID: 11668642 |
A possible hot spot in exon 21 of the retinoblastoma gene predisposing to a low penetrant retinoblastoma phenotype? | Ahmad NN | Ophthalmic genetics | 1999 | PMID: 10617920 |
Temperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families. | Otterson GA | American journal of human genetics | 1999 | PMID: 10486322 |
Twelve novel RB1 gene mutations in patients with hereditary retinoblastoma. Mutations in brief no. 206. Online. | Yilmaz S | Human mutation | 1998 | PMID: 10671068 |
A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype. | Cowell JK | Oncogene | 1998 | PMID: 9671401 |
Text-mined citations for rs137853296...
HelpThese 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 Jan 25, 2021