Genetic Variant RB1:p.Arg787* (chr13-48465238-C-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000321.3(RB1):c.2359C>T(p.Arg787*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RB1
NM_000321.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.20

Variant links:

Genes affected

RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

RB1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-48465238-C-T is Pathogenic according to our data. Variant chr13-48465238-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48465238-C-T is described in Lovd as [Pathogenic]. Variant chr13-48465238-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.2359C>T	p.Arg787*	stop_gained	Exon 23 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.2359C>T	p.Arg787*	stop_gained	Exon 23 of 27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RB1	ENST00000267163.6 link	c.2359C>T	p.Arg787*	stop_gained	Exon 23 of 27	1	NM_000321.3	ENSP00000267163.4	P06400
RB1	ENST00000650461.1 link	c.2359C>T	p.Arg787*	stop_gained	Exon 23 of 27			ENSP00000497193.1	A0A3B3IS71
RB1	ENST00000643064.1 link	c.192+83795C>T		intron_variant	Intron 1 of 1			ENSP00000496005.1	A0A2R8Y743

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Pathogenic:5

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg787*) 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: 2594029, 22328814, 24225018, 25602518, 26530098, 29568217). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13073). For these reasons, this variant has been classified as Pathogenic. -

Dec 21, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 20, 2024

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Case and Pedigree Information: BILATERAL CASES:16, UNILATERAL CASES:1, TOTAL CASES:17, PEDIGREES:17. ACMG Codes Applied:PVS1, PM2, PS4M -

May 13, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 09, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RB1 c.2359C>T (p.Arg787Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. This variant has been identified in multiple individuals with retinoblastoma (PMID: 2594029, 34277001, 29568217, 34580403, internal data) of which at least one case was assumed to be de novo. This variant is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -

not provided

Pathogenic:2

Nov 17, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 29568217, 2594029, 22328814, 32218800) -

May 29, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

May 02, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R787* pathogenic mutation (also known as c.2359C>T), located in coding exon 23 of the RB1 gene, results from a C to T substitution at nucleotide position 2359. This changes the amino acid from an arginine to a stop codon within coding exon 23. This alteration was first characterized in a patient diagnosed with bilateral retinoblastoma at six weeks of age (Yandell DW et al. N. Engl. J. Med. 1989 Dec;321(25):1689-95). It has subsequently been identified in multiple unrelated patients and families with retinoblastoma and retinocytoma (Alonso J et al. Hum. Mutat. 2005 Jan;25:99; Taylor M et al. Hum. Mutat. 2007 Mar; 28(3):284-93; Ahani A et al. Cancer Genet. 2011 Jun;204:316-22; Abouzeid H et al. Br J Ophthalmol. 2012 Jun;96(6):884-9; He MY et al. Mol. Vis. 2014;20:545-52; Sagi M et al. Fam. Cancer. 2015 Sep;14:471-80; Singh J et al. Mol. Vis. 2016 Aug;22:1036-47; Nguyen HH et al. Mol. Vis. 2018 Mar;24:231-23). 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. -

Malignant tumor of urinary bladder;C0035335:Retinoblastoma;C0149925:Small cell lung carcinoma;C0585442:Bone osteosarcoma

Pathogenic:1

Mar 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.88

Vest4

0.98

GERP RS

5.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over