13-48465238-C-T

Position:

• chr13-48465238-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.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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.20

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 13-48465238-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/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.2359C>T	p.Arg787*	stop_gained	23/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2359C>T	p.Arg787*	stop_gained	23/27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2359C>T	p.Arg787*	stop_gained	23/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.2359C>T	p.Arg787*	stop_gained	23/27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+83795C>T		intron_variant				ENSP00000496005.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461736 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

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.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 09, 2023	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. -
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:16, UNILATERAL CASES:1, TOTAL CASES:17, PEDIGREES:17. ACMG Codes Applied:PVS1, PM2, PS4M -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 21, 1989	- -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 29, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2021	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) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 04, 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	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.88	D
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

Other links and lift over

dbSNP: rs137853293; hg19: chr13-49039374; COSMIC: COSV57296164;