13-48381414-C-T

Variant names:

• chr13-48381414-C-T
• rs121913304
• NM_000321.3:c.1666C>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.1666C>T​(p.Arg556*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,322 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.68

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 13-48381414-C-T is Pathogenic according to our data. Variant chr13-48381414-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48381414-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.1666C>T	p.Arg556*	stop_gained	Exon 17 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1666C>T	p.Arg556*	stop_gained	Exon 17 of 27		NP_001394094.1
RB1	NM_001407166.1	c.1666C>T	p.Arg556*	stop_gained	Exon 17 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1666C>T	p.Arg556*	stop_gained	Exon 17 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1666C>T	p.Arg556*	stop_gained	Exon 17 of 27			ENSP00000497193.1
RB1	ENST00000643064.1	c.163C>T	p.Arg55*	stop_gained	Exon 1 of 2			ENSP00000496005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461322 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726954

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:3

Apr 18, 2024

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.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. -

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:6, UNILATERAL CASES:3, TOTAL CASES:9, PEDIGREES:9. ACMG Codes Applied:PVS1, PM2, PS4SUP -

Mar 11, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 24, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Trilateral retinoblastoma Pathogenic:1

Jan 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.98
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs121913304; hg19: chr13-48955550; COSMIC: COSV57296489;