13-48380062-C-T

Position:

• chr13-48380062-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.1399C>T​(p.Arg467*) 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: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RB1 NM_000321.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.32

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]

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 13-48380062-C-T is Pathogenic according to our data. Variant chr13-48380062-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 92839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48380062-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.1399C>T	p.Arg467*	stop_gained	15/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.1399C>T	p.Arg467*	stop_gained	15/27		NP_001394094.1
RB1	NM_001407166.1	c.1399C>T	p.Arg467*	stop_gained	15/17		NP_001394095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.1399C>T	p.Arg467*	stop_gained	15/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.1399C>T	p.Arg467*	stop_gained	15/27			ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1173832 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 585090

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: 0.00

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	Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	May 20, 2024	Case and Pedigree Information: BILATERAL CASES:8, UNILATERAL CASES:0, TOTAL CASES:8, PEDIGREES:8. ACMG Codes Applied:PVS1, PM2, PS4SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 01, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 92839). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 7795591, 24688104, 25928201, 26530098). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg467*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 03, 2023	The RB1 c.1399C>T variant is classified as Pathogenic (PVS1, PM2, PS4_moderate) The RB1 c.1399C>T variant is a single nucleotide change in exon 15/27 which is predicted to result in premature termination of the protein product at codon 467 (PVS1). The variant has been reported in multiple unrelated individuals with a clinical presentation of retinoblastoma (PMID: 7795591, 33456302, 24688104, 12541220) (PS4_Moderate). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs398123331) and in the HGMD database as disease causing (CM951106). It has been reported as pathogenic by other diagnostic laboratories (ClinVar Variation ID: 92839) and in the RB1 lsdb (RB1_000099). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 09, 2018	The p.Arg467X variant in RB1 has been reported in 8 individuals with retinoblastoma and segregated with disease in 1 affected relative (Blanquet 1995, Dommering 2014, Devarajan 2015, Grotta 2015). Of note, it was also present in one reportedly unaffected parent. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 467, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the RB1 gene is an established disease mechanism in retinoblastoma. In summary, the p.Arg467X variant meets criteria to be classified as pathogenic for retinoblastoma in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Dec 25, 2023	The RB1 c.1399C>T (p.Arg467Ter) 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 identified in multiple individuals with retinoblastoma (PMID: 25928201, 26530098, 33456302, 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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2022	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: 24078560, 21763628, 26530098, 17960112, 25525159, 25754945, 7795591, 24688104, 25928201, 27155049, 12541220, 23981928, 16343894, 26264229, 26084579, 20447117, 28803391, 33456302, 30787465) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 09, 2018	The p.R467* pathogenic mutation (also known as c.1399C>T), located in coding exon 15 of the RB1 gene, results from a C to T substitution at nucleotide position 1399. This changes the amino acid from an arginine to a stop codon within coding exon 15. This pathogenic mutation has been reported in numerous cases of both unilateral and bilateral retinoblastoma (Blanquet V et al. Hum. Mol. Genet. 1995 Mar; 4(3):383-8; 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; Houdayer C et al. Hum Mutat. 2004 Feb;23(2):193-202; Taylor M et al. Hum Mutat. 2007 Mar;28(3):284-93). This mutation has been referred to as g.76898C>T in the literature. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 24, 2017	Variant summary: The RB1 c.1399C>T (p.Arg467X) variant results in a premature termination codon, predicted to cause a truncated or absent RB1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate Retinoblastoma-associated protein, A-box, Retinoblastoma-associated protein, B-box and Retinoblastoma-associated protein, C-terminal (via InterPro). Truncations downstream of this position have been classified as pathogenic clinical laboratories in ClinVar (e.g. p.Gln504Ter, p.Trp563Ter, p.Gln850Ter, etc). This variant is absent in 24658 control chromosomes from ExAC. In literature, this variant is reported as a recurrent pathogenic variant that causes retinoblastoma. The variant is found as germline as well as somatic variant in retinoblastoma patients. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.96
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs398123331; hg19: chr13-48954198; COSMIC: COSV57296693; COSMIC: COSV57296693;