13-48453032-C-T

Position:

• chr13-48453032-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.1735C>T​(p.Arg579*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,884 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:7
• Conservation: PhyloP100: 1.32

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 (HGNC:):

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 13-48453032-C-T is Pathogenic according to our data. Variant chr13-48453032-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 126785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48453032-C-T is described in Lovd as [Pathogenic]. Variant chr13-48453032-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.1735C>T	p.Arg579*	stop_gained	18/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1735C>T	p.Arg579*	stop_gained	18/27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1735C>T	p.Arg579*	stop_gained	18/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1735C>T	p.Arg579*	stop_gained	18/27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+71589C>T		intron_variant				ENSP00000496005.1
RB1	ENST00000480491.1	n.434C>T		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460884 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726766

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2023	This sequence change creates a premature translational stop signal (p.Arg579*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 126785). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 7704558, 12541220, 25754945, 27021801, 27582626; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -
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:20, UNILATERAL CASES:3, TOTAL CASES:23, PEDIGREES:22 (one pedigree contains both unilateral and bilateral cases). ACMG Codes Applied:PVS1, PM2, PS4S -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 22, 2023	The RB1 c.1735C>T (p.Arg579Ter) 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: 8651278, 12541220, 15166261, 17096365, internal data). 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	Genetics and Molecular Pathology, SA Pathology	May 16, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Mar 08, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 25, 2020

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, 24810223, 12187430, 27021801, 21763628, 17250439, 7704558, 7795591, 23301675, 25754945, 17960112, 12541220, 15605413, 24791139, 16343894, 25157968, 28449824, 20447117, 19280657, 25236499, 23981928, 27582626, 28803391, 9311732, 26539030, 33456302) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2024

The p.R579* pathogenic mutation (also known as c.1735C>T), located in coding exon 18 of the RB1 gene, results from a C to T substitution at nucleotide position 1735. This changes the amino acid from an arginine to a stop codon within coding exon 18. This alteration has been described in many patients with bilateral and unilateral retinoblastoma and is considered a common and recurrent RB1 mutation (Lohmann DR et al. Am J Hum Genet. 1996 May;58(5):940-9; Richter S et al. Am. J. Hum. Genet. 2003 Feb; 72(2):253-69; Braggio E et al. J Clin Pathol. 2004 Jun;57(6):585-90; Saliminejad K et al. J. Genet. 2013 ; 92(2):e36-40; Yousef YA et al. Fam Cancer. 2018 Apr;17(2):261-268). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.57	D
Vest4		0.95
GERP RS		1.8

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: rs121913305; hg19: chr13-49027168; COSMIC: COSV57294317;