Genetic Variant RB1:p.Arg552* (chr13-48381402-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.1654C>T(p.Arg552*) 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 1,461,280 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.59

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 13-48381402-C-T is Pathogenic according to our data. Variant chr13-48381402-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 126840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48381402-C-T is described in Lovd as [Pathogenic]. Variant chr13-48381402-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.1654C>T	p.Arg552*	stop_gained	Exon 17 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.1654C>T	p.Arg552*	stop_gained	Exon 17 of 27		NP_001394094.1
RB1	NM_001407166.1 link	c.1654C>T	p.Arg552*	stop_gained	Exon 17 of 17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RB1	ENST00000267163.6 link	c.1654C>T	p.Arg552*	stop_gained	Exon 17 of 27	1	NM_000321.3	ENSP00000267163.4	P06400
RB1	ENST00000650461.1 link	c.1654C>T	p.Arg552*	stop_gained	Exon 17 of 27			ENSP00000497193.1	A0A3B3IS71
RB1	ENST00000643064.1 link	c.151C>T	p.Arg51*	stop_gained	Exon 1 of 2			ENSP00000496005.1	A0A2R8Y743

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461280

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726942

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinoblastoma

Pathogenic:4

May 01, 2024

Swedish National ChiCaP Initative, Genomic Medicine Sweden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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:4, TOTAL CASES:10, PEDIGREES:10. ACMG Codes Applied:PVS1, PM2, PS4M -

Aug 08, 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.Arg552*) 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: 7704558, 22219649, 24791139, 25754945, 27582626). ClinVar contains an entry for this variant (Variation ID: 126840). For these reasons, this variant has been classified as Pathogenic. -

Dec 15, 2020

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Malignant tumor of urinary bladder

Pathogenic:1

Laboratory of Urology, Hospital Clinic de Barcelona

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Pathogenic:1

May 01, 2024

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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 7704558, 19280657, 15166261, 34308366, 31772335, 25157968, 37658463, 32434110, 24791139, 27582626, 28873162, 37548407, 34680218, 32835838, Moghadam2022[article], 34645364, 25754945, 34294096, 33466343, 16343894, 33456302, 9311732, 12541220, 22219649, 28575107) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Nov 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R552* pathogenic mutation (also known as c.1654C>T), located in coding exon 17 of the RB1 gene, results from a C to T substitution at nucleotide position 1654. This changes the amino acid from an arginine to a stop codon within coding exon 17. This alteration, often designated as "R552X" in published literature, has been detected in the germline of multiple patients diagnosed with bilateral retinoblastoma, and has been confirmed as a somatic mutation in RB tumor DNA in other patients (Braggio E et al. J Clin Pathol. 2004 Jun;57(6):585-90; Richter S et al. Am J Hum Genet. 2003 Feb;72(2):253-69; He MY et al. Mol Vis. 2014 Apr 25;20:545-52). 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

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.81

Vest4

0.93

GERP RS

1.2

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

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