VCV000013090.14 - ClinVar

NM_000321.3(RB1):c.1666C>T (p.Arg556Ter)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000321.3(RB1):c.1666C>T (p.Arg556Ter)

Variation ID: 13090 Accession: VCV000013090.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q14.2 13: 48381414 (GRCh38) [ NCBI UCSC ] 13: 48955550 (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	Apr 19, 2014	Jun 2, 2024	May 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000321.3:c.1666C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000312.2:p.Arg556Ter	nonsense
NC_000013.11:g.48381414C>T
NC_000013.10:g.48955550C>T
NG_009009.1:g.82668C>T
LRG_517:g.82668C>T
LRG_517t1:c.1666C>T	LRG_517p1:p.Arg556Ter

... more HGVS ... less HGVS

Protein change

R556*

Other names

L11910:g.78250C>T

Canonical SPDI

NC_000013.11:48381413:C:T

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.

Links

ClinGen: CA026386 OMIM: 614041.0022 dbSNP: rs121913304 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.
RB1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3632	3793

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.
Trilateral retinoblastoma	Pathogenic (1)	no assertion criteria provided	Jan 1, 1997	RCV000013966.3
Retinoblastoma	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 20, 2024	RCV000114734.12
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Nov 24, 2021	RCV000492084.3
Neoplasm	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000430238.1

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 (Mar 11, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinoblastoma Affected status: yes Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV000853194.1 First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018	Comment: This is a nonsense variant in which a C is replaced by a T at coding position 1666 and is predicted to change an Arginine … (more) This is a nonsense variant in which a C is replaced by a T at coding position 1666 and is predicted to change an Arginine to a premature stop codon at codon 556. (less) Sex: male
Pathogenic (May 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinoblastoma Affected status: yes Allele origin: germline	Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine Accession: SCV000087407.2 First in ClinVar: Apr 19, 2014 Last updated: Jun 02, 2024	Comment: Case and Pedigree Information: BILATERAL CASES:6, UNILATERAL CASES:3, TOTAL CASES:9, PEDIGREES:9. ACMG Codes Applied:PVS1, PM2, PS4SUP Number of individuals with the variant: 9
Pathogenic (Dec 07, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Retinoblastoma Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000551823.9 First in ClinVar: Apr 19, 2014 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 28492532‚ 17096365‚ 22963398‚ 24688104‚ 25602518 Comment: This sequence change creates a premature translational stop signal (p.Arg556) in the RB1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg556) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 22963398, 24688104, 25602518). ClinVar contains an entry for this variant (Variation ID: 13090). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 24, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000580816.6 First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 16463005‚ 21763628‚ 22963398‚ 30031154‚ 33456302‚ 8605116‚ 9400934 Comment: The p.R556* pathogenic mutation (also known as c.1666C>T), located in coding exon 17 of the RB1 gene, results from a C to T substitution at … (more) The p.R556* pathogenic mutation (also known as c.1666C>T), located in coding exon 17 of the RB1 gene, results from a C to T substitution at nucleotide position 1666. This changes the amino acid from an arginine to a stop codon within coding exon 17. This mutation has been reported in multiple patients with bilateral retinoblastoma (Onadim Z et al. Br. J. Cancer 1997; 76(11):1405-9; Sampieri K et al. J. Hum. Genet. 2006 ; 51(3):209-16; Seo SH et al. Clin. Genet. 2013 May; 83(5):494-6; Zou Y et al. Mol Vis, 2021 Jan;27:1-16). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Likely pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	Neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000505676.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 25157968 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000267163:c.1666C>T
Pathogenic (Jan 01, 1997)	no assertion criteria provided Method: literature only	RETINOBLASTOMA, TRILATERAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034213.2 First in ClinVar: Apr 04, 2013 Last updated: Feb 01, 2018	Publications: PubMed (4) PubMed: 9400934‚ 8346255‚ 7704558‚ 8605116 Comment on evidence: In a child with ectopic intracranial retinoblastoma, Onadim et al. (1997) found a nonsense mutation in exon 17 (codon 556) of the RB1 gene in … (more) In a child with ectopic intracranial retinoblastoma, Onadim et al. (1997) found a nonsense mutation in exon 17 (codon 556) of the RB1 gene in homozygous (or hemizygous) state in both the retinal and the pineal tumors (180200). Diagnosis of bilateral retinoblastoma was made at the age of 13 months; the patient presented with the pineal tumor 32 months after the initial diagnosis of retinoblastoma. The RB1 mutation was a C-to-T transition (CGA to TGA) within a CpG dinucleotide, converting an arginine codon to a stop codon (R556X). The mutation occurred in a region of the gene that codes for part of the 'pocket' region of the Rb protein. The mutation was present heterozygously in the DNA from the constitutional cells of the patient. The mutation was absent in the blood DNA of both the father and the mother, and was shown to have occurred on the copy of the RB1 gene derived from the father. This mutation had been reported by Hogg et al. (1993) in the retinal tumor from a unilateral nonhereditary case of retinoblastoma. The same mutation was identified as a germline mutation by Cowell et al. (1994) and Liu et al. (1995). (less)

Comment:

This sequence change creates a premature translational stop signal (p.Arg556*) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 22963398, 24688104, 25602518). ClinVar contains an entry for this variant (Variation ID: 13090). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.R556* pathogenic mutation (also known as c.1666C>T), located in coding exon 17 of the RB1 gene, results from a C to T substitution at nucleotide position 1666. This changes the amino acid from an arginine to a stop codon within coding exon 17. This mutation has been reported in multiple patients with bilateral retinoblastoma (Onadim Z et al. Br. J. Cancer 1997; 76(11):1405-9; Sampieri K et al. J. Hum. Genet. 2006 ; 51(3):209-16; Seo SH et al. Clin. Genet. 2013 May; 83(5):494-6; Zou Y et al. Mol Vis, 2021 Jan;27:1-16). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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
Spectrum of germline mutations in RB1 in Chinese patients with retinoblastoma: Application of targeted next-generation sequencing.	Zou Y	Molecular vision	2021	PMID: 33456302
Correlation between RB1germline mutations and second primary malignancies in hereditary retinoblastoma patients treated with external beam radiotherapy.	Chaussade A	European journal of medical genetics	2019	PMID: 30031154
Mutation spectrum of RB1 gene in unilateral retinoblastoma cases from Tunisia and correlations with clinical features.	Ayari-Jeridi H	PloS one	2015	PMID: 25602518
Prospective enterprise-level molecular genotyping of a cohort of cancer patients.	MacConaill LE	The Journal of molecular diagnostics : JMD	2014	PMID: 25157968
RB1 mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients.	Dommering CJ	Journal of medical genetics	2014	PMID: 24688104
Mutation spectrum of RB1 gene in Korean bilateral retinoblastoma patients using direct sequencing and gene dosage analysis.	Seo SH	Clinical genetics	2013	PMID: 22963398
RB1 gene mutations in Iranian patients with retinoblastoma: report of four novel mutations.	Ahani A	Cancer genetics	2011	PMID: 21763628
Genotype-phenotype correlations in hereditary familial retinoblastoma.	Taylor M	Human mutation	2007	PMID: 17096365
Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations.	Sampieri K	Journal of human genetics	2006	PMID: 16463005
The RB1 gene mutation in a child with ectopic intracranial retinoblastoma.	Onadim Z	British journal of cancer	1997	PMID: 9400934
Germline mutations in the RB1 gene in patients with hereditary retinoblastoma.	Liu Z	Genes, chromosomes & cancer	1995	PMID: 8605116
Frequent constitutional C to T mutations in CGA-arginine codons in the RB1 gene produce premature stop codons in patients with bilateral (hereditary) retinoblastoma.	Cowell JK	European journal of human genetics : EJHG	1994	PMID: 7704558
Molecular mechanisms of oncogenic mutations in tumors from patients with bilateral and unilateral retinoblastoma.	Hogg A	Proceedings of the National Academy of Sciences of the United States of America	1993	PMID: 8346255
http://docm.genome.wustl.edu/variants/ENST00000267163:c.1666C>T	-	-	-	-
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Text-mined citations for rs121913304 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000321.3(RB1):c.1666C>T (p.Arg556Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913304 ...