NM_000321.3(RB1):c.137G>C (p.Arg46Thr) AND Retinoblastoma

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 20, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002013754.6

Allele description [Variation Report for NM_000321.3(RB1):c.137G>C (p.Arg46Thr)]

NM_000321.3(RB1):c.137G>C (p.Arg46Thr)

Gene:

RB1:RB transcriptional corepressor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q14.2

Genomic location:

Preferred name:

NM_000321.3(RB1):c.137G>C (p.Arg46Thr)

HGVS:

NC_000013.11:g.48304049G>C
NG_009009.1:g.5303G>C
NM_000321.3:c.137G>CMANE SELECT
NP_000312.2:p.Arg46Thr
LRG_517:g.5303G>C
NC_000013.10:g.48878185G>C

Protein change:

R46T

Links:

dbSNP: rs2138028088

NCBI 1000 Genomes Browser:

rs2138028088

Molecular consequence:

NM_000321.3:c.137G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Retinoblastoma (RB1)
Synonyms:: Eye cancer, retinoblastoma; RETINOBLASTOMA, SOMATIC
Identifiers:: MONDO: MONDO:0008380; MeSH: D012175; MedGen: C0035335; Orphanet: 790; OMIM: 180200; Human Phenotype Ontology: HP:0009919

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002307138	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 4, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17576681, 9536098, 15884040, 28492532
SCV005046045	Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 20, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002307138

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 4, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV005046045

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 20, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002307138.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) bilateral retinoblastoma (PMID: 15884040). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces arginine with threonine at codon 46 of the RB1 protein (p.Arg46Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine, SCV005046045.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

Description

Case and Pedigree Information: BILATERAL CASES:3, UNILATERAL CASES:0, TOTAL CASES:3, PEDIGREES:3. ACMG Codes Applied:PVS1, PM2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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