13-48463758-T-C

Variant names:

• chr13-48463758-T-C
• rs137853296
• NM_000321.3:c.2134T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000321.3(RB1):​c.2134T>C​(p.Cys712Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C712G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.65
• Publications: 14 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 13-48463758-T-C is Pathogenic according to our data. Variant chr13-48463758-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13092.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.2134T>C	p.Cys712Arg	missense	Exon 21 of 27	NP_000312.2
	RB1	NM_001407165.1		c.2134T>C	p.Cys712Arg	missense	Exon 21 of 27	NP_001394094.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.2134T>C	p.Cys712Arg	missense	Exon 21 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*1502T>C		non_coding_transcript_exon	Exon 16 of 22	ENSP00000434702.1
	RB1	ENST00000467505.6	TSL:1	n.*1502T>C		3_prime_UTR	Exon 16 of 22	ENSP00000434702.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000520 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:3

Sep 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 13092). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RB1 function (PMID: 10486322, 18677112). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RB1 protein function. This missense change has been observed in individuals with retinoblastoma (PMID: 9671401, 10617920, 10671068, 11668642, 12541220, 16269091, 22084214). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 712 of the RB1 protein (p.Cys712Arg).

Oct 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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:1, UNILATERAL CASES:4, TOTAL CASES:5, PEDIGREES:5. ACMG Codes Applied:PM2, PS4M, PP3, PP5

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 09, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C712R variant (also known as c.2134T>C), located in coding exon 21 of the RB1 gene, results from a T to C substitution at nucleotide position 2134. The cysteine at codon 712 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported to be associated with a low penetrant phenotype since it has been identified in multiple families with cases of unilateral or regressed tumors and/or unaffected individuals considered at risk for retinoblastoma (Cowell J et al Oncogene. 1998 Jun 18;16(24):3211-3; Valverde J et al BMC Genet. 2005 Nov 4;6:53; Richter S et al Am J Hum Genet. 2003 Feb;72(2):253-69). This variant is located in the A/B pocket and intervening spacer region of the RB1 protein, a critical region of RB1 (Richter S et al Am J Hum Genet. 2003 Feb;72(2):253-69). While alterations to a critical region of the gene are often deleterious, the temperature-sensitive pocket activity of the RB1 gene may explain the observed low penetrance of the C712R alteration (Valverde J et al BMC Genet. 2005 Nov 4;6:53). This amino acid position is highly conserved in available vertebrate species. This splice prediction software does not predict a deleterious effect on splicing. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Hereditary retinoblastoma Pathogenic:1

Nov 21, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.83		Gain of catalytic residue at S707 (P = 0)
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.99
gMVP		0.95
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs137853296; hg19: chr13-49037894;