13-48367512-C-T

Variant names:

• chr13-48367512-C-T
• rs121913300
• NM_000321.3:c.958C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000321.3(RB1):​c.958C>T​(p.Arg320*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,222 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R320R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.08
• Publications: 52 publications found

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 Gene-Disease associations (from GenCC):

• hereditary retinoblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

LOC112268118 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 13-48367512-C-T is Pathogenic according to our data. Variant chr13-48367512-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 126824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.958C>T	p.Arg320*	stop_gained	Exon 10 of 27	NP_000312.2
	RB1	NM_001407165.1		c.958C>T	p.Arg320*	stop_gained	Exon 10 of 27	NP_001394094.1
	RB1	NM_001407166.1		c.958C>T	p.Arg320*	stop_gained	Exon 10 of 17	NP_001394095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.958C>T	p.Arg320*	stop_gained	Exon 10 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*326C>T		non_coding_transcript_exon	Exon 5 of 22	ENSP00000434702.1
	RB1	ENST00000467505.6	TSL:1	n.*326C>T		3_prime_UTR	Exon 5 of 22	ENSP00000434702.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451222 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721618

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33260

American (AMR) AF: 0.00 AC: 0 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 39244

South Asian (SAS) AF: 0.00 AC: 0 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105762

Other (OTH) AF: 0.00 AC: 0 AN: 59818

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000190 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:4

Mar 22, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RB1 c.958C>T variant is classified as pathogenic (PVS1, PM6, PS4, PM2, PM3) The RB1 c.958C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 320 (PVS1). This variant has been identified as a de novo variant in at least four unrelated patients (PMID:33456302) (PM6). The variant has been widely reported in patients with retinoblastoma, both as germline, somatic and mosaic(PMID:33456302, PMID:28575107) (PS4). This variant is absent from population databases (PM2). This variant has been detected in trans with a somatic pathogenic variant (PMID:28575107) (PM3). The variant has been reported in dbSNP (rs121913300) and in the HGMD database as disease causing (CM941205). It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 126824) and in the RB1 variant database (LOVD RB1-000072).

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:20, UNILATERAL CASES:2, TOTAL CASES:22, PEDIGREES:22. ACMG Codes Applied:PVS1, PM2, PS4S

Dec 15, 2020

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Nov 05, 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.Arg320*) 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 bilateral retinoblastoma and retinoblastoma (PMID: 7704558, 12541220, 15605413, 24225018, 24810223, 25754945, 28575107). In at least one individual the variant was observed to be de novo. This variant is also known as g.64348C>T. ClinVar contains an entry for this variant (Variation ID: 126824). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1

Mar 22, 2023

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 in large population cohorts (gnomAD); Observed in multiple individuals with retinoblastoma (Lohmann et al., 1996; Choy et al., 2002; Alonso et al., 2005; Sagi et al., 2015; Tomar et al., 2017); This variant is associated with the following publications: (PMID: 19280657, 34190019, 8651278, 12402348, 33493472, 7704558, 28575107, 25754945, 12541220, 15605413, 27983729, 14722923, 18840911, 34308366, 34294096, 33456302, 31772335, 34277001, 34645364, 35960463, 33318192)

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 30, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R320* pathogenic mutation (also known as c.958C>T), located in coding exon 10 of the RB1 gene, results from a C to T substitution at nucleotide position 958. This changes the amino acid from an arginine to a stop codon within coding exon 10. This mutation has been reported in numerous individuals affected with sporadic and familial retinoblastoma both bilaterally and unilaterally (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; Alonso J et al. Hum. Mutat. 2005 Jan;25(1):99; Choy KW et al. Hum. Mutat. 2002 Nov;20(5):408; Houdayer C et al. Hum. Mutat. 2004 Feb; 23(2):193-202). 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 v4.9

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	0.91
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		3.1
Vest4		0.96
GERP RS		5.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121913300; hg19: chr13-48941648; COSMIC: COSV57297576; COSMIC: COSV57297576;