13-48362847-C-T

Position:

• chr13-48362847-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.751C>T​(p.Arg251*) 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:6 O:1
• Conservation: PhyloP100: 2.82

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 13-48362847-C-T is Pathogenic according to our data. Variant chr13-48362847-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 428681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48362847-C-T is described in Lovd as [Pathogenic]. Variant chr13-48362847-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.751C>T	p.Arg251*	stop_gained	8/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.751C>T	p.Arg251*	stop_gained	8/27		NP_001394094.1
RB1	NM_001407166.1	c.751C>T	p.Arg251*	stop_gained	8/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.751C>T	p.Arg251*	stop_gained	8/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000467505.5	n.*119C>T		non_coding_transcript_exon_variant	3/3	1		ENSP00000434702.1
RB1	ENST00000467505.5	n.*119C>T		3_prime_UTR_variant	3/3	1		ENSP00000434702.1
RB1	ENST00000650461.1	c.751C>T	p.Arg251*	stop_gained	8/27			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:5

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:11, UNILATERAL CASES:2, TOTAL CASES:13, PEDIGREES:12 (one pedigree contains both unilateral and bilateral cases). ACMG Codes Applied:PVS1, PM2, PS4M -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Nov 12, 2024	The RB1 c.751C>T (p.Arg251Ter) change is a nonsense variant that is predicted to cause premature protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in individuals with retinoblastoma (PMID: 25928201, 33456302, internal data). This variant is also absent in gnomAD v2.1.1. In summary, this variant meets criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 03, 2023	The RB1 c.751C>T variant is classified as Pathogenic (PVS1, PM2, PS4_moderate) The RB1 c.751C>T variant is a single nucleotide change in exon 8/27 which is predicted to result in premature termination of the protein product at codon 251 (PVS1). The variant has been reported in multiple unrelated individuals with a clinical presentation of retinoblastoma (PMID: 8651278, 14722923, 17096365, 34294096) (PS4_Moderate). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs1131690863) and in the HGMD database as disease causing (CM941204). It has been reported as pathogenic by other diagnostic laboratories (ClinVar Variation ID: 428681) and in the RB1 lsdb (RB1_000062). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 428681). This premature translational stop signal has been observed in individual(s) with familial and sporadic retinoblastoma (PMID: 7704558, 22963398, 23595191, 24688104, 24791139, 25754945, 25928201, 26396485, 26539030, 27582626). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg251*) 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2021

The p.R251* pathogenic mutation (also known as c.751C>T), located in coding exon 8 of the RB1 gene, results from a C to T substitution at nucleotide position 751. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has been reported in multiple patients diagnosed unilateral or bilateral retinoblastoma (Shahraki K et al. Eye (Lond). 2017 Apr;31:620-627; He MY et al. Mol Vis. 2014 Apr;20:545-52; Saliminejad K et al. J. Genet. 2013 May;92:e36-40; Ahani A et al. Cancer Genet. 2011 Jun;204:316-22; Pradhan MA et al. Clin. Experiment. Ophthalmol. 2010 Apr;38:231-6; Abouzeid H et al. Mol. Vis. 2007 Sep;13:1740-5; Houdayer C et al. Hum. Mutat. 2004 Feb;23:193-202; Lohmann DR et al. Am. J. Hum. Genet. 1996 May;58:940-9). Of note, this mutation is also designated as g.59683C>T in some published literature. This variant was not reported in population-based 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. -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.82	D
Vest4		0.95
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1131690863; hg19: chr13-48936983; COSMIC: COSV57294817; COSMIC: COSV57294817;