13-48360118-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000321.3(RB1):c.709G>T(p.Glu237*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000321.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.709G>T | p.Glu237* | stop_gained | Exon 7 of 27 | ENST00000267163.6 | NP_000312.2 | |
RB1 | NM_001407165.1 | c.709G>T | p.Glu237* | stop_gained | Exon 7 of 27 | NP_001394094.1 | ||
RB1 | NM_001407166.1 | c.709G>T | p.Glu237* | stop_gained | Exon 7 of 17 | NP_001394095.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:1
This sequence change creates a premature translational stop signal (p.Glu237*) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 23532519, 24225018). ClinVar contains an entry for this variant (Variation ID: 428731). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.E237* pathogenic mutation (also known as c.709G>T), located in coding exon 7 of the RB1 gene, results from a G to T substitution at nucleotide position 709. This changes the amino acid from a glutamic acid to a stop codon within coding exon 7. This mutation has been detected in one individual with bilateral retinoblastoma (RB) and leukemia and was also detected in one individual from a cohort of patients with with either bilateral and/or familial RB or unilateral sporadic RB (Barbosa RH, et al. Invest. Ophthalmol. Vis. Sci. 2013; 54(5):3184-94, Price EA, et al. J. Med. Genet. 2014; 51(3):208-14). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at