13-48307352-CAG-C

Position:

• chr13-48307352-CAG-C

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.219_220del​(p.Arg73SerfsTer36) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.28

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 13-48307352-CAG-C is Pathogenic according to our data. Variant chr13-48307352-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 126844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-48307352-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.219_220del	p.Arg73SerfsTer36	frameshift_variant	2/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.219_220del	p.Arg73SerfsTer36	frameshift_variant	2/27		NP_001394094.1
RB1	NM_001407166.1	c.219_220del	p.Arg73SerfsTer36	frameshift_variant	2/17		NP_001394095.1
RB1	NM_001407167.1	c.219_220del	p.Arg73SerfsTer44	frameshift_variant	2/3		NP_001394096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.219_220del	p.Arg73SerfsTer36	frameshift_variant	2/27	1	NM_000321.3	ENSP00000267163	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2020	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant has been observed in individuals affected with retinoblastoma (PMID: 12541220, 15884040). This variant is also known as 350delGA or g.5497delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 126844). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg73Serfs*36) in the RB1 gene. It is expected to result in an absent or disrupted protein product. -
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:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PVS1, PM2 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2015

The c.219_220delAG pathogenic mutation, located in coding exon 2 of the RB1 gene, results from a deletion of two nucleotides at positions 219 and 220, causing a translational frameshift with a predicted alternate stop codon. This alteration (designated as 350delGA) has been previously identified in one individual with retinoblastoma (Richter S, Am. J. Hum. Genet. 2003 Feb; 72(2):253-69). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

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: rs587778862; hg19: chr13-48881488;