VCV000013092.4 - ClinVar

NM_000321.2(RB1):c.2134T>C (p.Cys712Arg)

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

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 consequence
NC_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

... more HGVS ... less HGVS

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

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
Retinoblastoma	Pathogenic	2	criteria provided, single submitter	Mar 28, 2019	RCV000013968.3
Hereditary cancer-predisposing syndrome	Likely pathogenic	1	criteria provided, single submitter	Mar 9, 2018	RCV000492516.2

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
RB1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1114	1199

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	Supporting information (See all)
Pathogenic (Mar 28, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Retinoblastoma Allele origin: germline	Invitae Accession: SCV001224741.1 Submitted: (Feb 06, 2020)	Evidence details Publications PubMed (9) 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 (Ambry Autosomal Dominant and X-Linked criteria (3/2017)) Method: clinical testing	Hereditary cancer-predisposing syndrome Allele origin: germline	Ambry Genetics Accession: SCV000580826.4 Submitted: (Nov 30, 2020)	Evidence details Publications PubMed (4) 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)	Evidence details Publications PubMed (1)

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 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.

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 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.

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 this variant

Title	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...

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 Jan 25, 2021

ClinVar Genomic variation as it relates to human health

NM_000321.2(RB1):c.2134T>C (p.Cys712Arg)

NM_000321.2(RB1):c.2134T>C (p.Cys712Arg)

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs137853296...