chr13-48362859-C-T

Position:

• chr13-48362859-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000321.3(RB1):​c.763C>T​(p.Arg255*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: RB1 NM_000321.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.13

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]

ACMG classification

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 13-48362859-C-T is Pathogenic according to our data. Variant chr13-48362859-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 126820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48362859-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.763C>T	p.Arg255*	stop_gained	8/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.763C>T	p.Arg255*	stop_gained	8/27		NP_001394094.1
RB1	NM_001407166.1	c.763C>T	p.Arg255*	stop_gained	8/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.763C>T	p.Arg255*	stop_gained	8/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000467505.5	n.*131C>T		non_coding_transcript_exon_variant	3/3	1		ENSP00000434702.1
RB1	ENST00000467505.5	n.*131C>T		3_prime_UTR_variant	3/3	1		ENSP00000434702.1
RB1	ENST00000650461.1	c.763C>T	p.Arg255*	stop_gained	8/27			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:6

Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2023	This sequence change creates a premature translational stop signal (p.Arg255*) 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 individuals with retinoblastoma (PMID: 7704558, 22963398, 24225018, 25754945, 27155049). ClinVar contains an entry for this variant (Variation ID: 126820). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	May 20, 2024	Case and Pedigree Information: BILATERAL CASES:14, UNILATERAL CASES:2, TOTAL CASES:16, PEDIGREES:15. ACMG Codes Applied:PVS1, PM2, PS4M -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2021	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Aug 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 27, 2022	The RB1 c.763C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) The RB1 c.763C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 255 (PVS1). The variant has been reported in probands with a clinical presentation of either sporadic or familial retinoblastoma (PS4_Moderate). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs587778842) and in the HGMD database: CM951104. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 126820). -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Oct 12, 2022	PVS1, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Apr 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 24, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The p.R255* pathogenic mutation (also known as c.763C>T), located in coding exon 8 of the RB1 gene, results from a C to T substitution at nucleotide position 763. This changes the amino acid from an arginine to a stop codon within coding exon 8. This alteration has been reported in multiple individuals with either sporadic or familial retinoblastoma (Zhang L et al. Tumour Biol. 2015 Apr;36:2409-20; Thirumalairaj K et al. J. Hum. Genet. 2015 Sep;60:547-52; Taylor M et al. Hum. Mutat. 2007 Mar;28:284-93; Rushlow D et al. Hum. Mutat. 2009 May;30:842-51; Sagi M et al. Fam. Cancer. 2015 Sep;14:471-80; Blanquet V et al. Hum. Mol. Genet. 1994 Jul;3:1185-6). Some individuals with sporadic retinoblastoma were found to be mosaic for this alteration (Rushlow D et al. Hum. Mutat. 2009 May;30:842-51; Sagi M et al. Fam. Cancer. 2015 Sep;14:471-80). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.76	D
Vest4		0.93
GERP RS		3.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

Other links and lift over

dbSNP: rs587778842; hg19: chr13-48936995; COSMIC: COSV57299867; COSMIC: COSV57299867;