13-48465046-G-C

Variant names:

• chr13-48465046-G-C
• rs587778642
• NM_000321.3:c.2260G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000321.3(RB1):​c.2260G>C​(p.Val754Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000074 in 1,350,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V754A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:1
• Conservation: PhyloP100: 6.49
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2260G>C	p.Val754Leu	missense	Exon 22 of 27	NP_000312.2
	RB1	NM_001407165.1		c.2260G>C	p.Val754Leu	missense	Exon 22 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.2260G>C	p.Val754Leu	missense	Exon 22 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.*1628G>C		non_coding_transcript_exon	Exon 17 of 22	ENSP00000434702.1
	RB1	ENST00000467505.6	TSL:1	n.*1628G>C		3_prime_UTR	Exon 17 of 22	ENSP00000434702.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 7.40e-7 AC: 1 AN: 1350728 Hom.: 0 Cov.: 36 AF XY: 0.00000149 AC XY: 1 AN XY: 670438

African (AFR) AF: 0.00 AC: 0 AN: 30806

American (AMR) AF: 0.00 AC: 0 AN: 41124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21642

East Asian (EAS) AF: 0.00 AC: 0 AN: 30898

South Asian (SAS) AF: 0.00 AC: 0 AN: 85202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4840

European-Non Finnish (NFE) AF: 9.63e-7 AC: 1 AN: 1037956

Other (OTH) AF: 0.00 AC: 0 AN: 52890

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:2

Jan 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 754 of the RB1 protein (p.Val754Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 135124). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RB1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Aug 08, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with leucine at codon 754 of the RB1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant (same amino acid change, different nucleotide change) has been reported in individuals affected with retinoblastoma (PMID: 34456592). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

not provided Uncertain:2

Dec 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RB1 c.2260G>C; p.Val754Leu variant (rs587778642), to our knowledge, is not reported in the medical literature in individuals affected with an RB1-related condition but is reported in ClinVar (Variation ID: 135124). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.551). Due to limited information, the clinical significance of this variant is uncertain at this time.

Oct 03, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with unilateral retinoblastoma and no relevant family history, as well as healthy individuals undergoing whole genome sequencing (Bodian et al., 2014; Xie et al., 2021); This variant is associated with the following publications: (PMID: 24728327, 34456592)

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V754L variant (also known as c.2260G>C), located in coding exon 22 of the RB1 gene, results from a G to C substitution at nucleotide position 2260. The valine at codon 754 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.55
Sift	Benign	0.083	T
Sift4G	Uncertain	0.038	D
Polyphen		0.93	P
Vest4		0.29
MutPred		0.57		Gain of catalytic residue at N757 (P = 0)
MVP		0.85
MPC		1.3
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.63
gMVP		0.56
Mutation Taster		=33/67	disease causing

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: rs587778642; hg19: chr13-49039182;