13-48465046-G-C

Position:

• chr13-48465046-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★★).

• 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:4 O:1
• Conservation: PhyloP100: 6.49

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.2260G>C	p.Val754Leu	missense_variant	22/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2260G>C	p.Val754Leu	missense_variant	22/27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2260G>C	p.Val754Leu	missense_variant	22/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.2260G>C	p.Val754Leu	missense_variant	22/27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+83603G>C		intron_variant				ENSP00000496005.1

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

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: 9.63e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 08, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2024

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

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.4	M;.
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);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs587778642; hg19: chr13-49039182; COSMIC: COSV57317933;