13-48456349-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000321.3(RB1):c.1960G>C(p.Val654Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V654A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000321.3 missense, splice_region
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.1960G>C | p.Val654Leu | missense_variant, splice_region_variant | 19/27 | ENST00000267163.6 | |
RB1 | NM_001407165.1 | c.1960G>C | p.Val654Leu | missense_variant, splice_region_variant | 19/27 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.1960G>C | p.Val654Leu | missense_variant, splice_region_variant | 19/27 | 1 | NM_000321.3 | P1 | |
RB1 | ENST00000650461.1 | c.1960G>C | p.Val654Leu | missense_variant, splice_region_variant | 19/27 | ||||
RB1 | ENST00000643064.1 | c.194+74906G>C | intron_variant | ||||||
RB1 | ENST00000480491.1 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2019 | This sequence change replaces valine with leucine at codon 654 of the RB1 protein (p.Val654Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant also falls at the last nucleotide of exon 19 of the RB1 coding sequence, which is part of the consensus splice site for this exon. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1960G nucleotide in the RB1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 22084214, 14722923, 15884040, 18449911). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 18449911). This variant has been observed in individuals affected with retinoblastoma (PMID: 19280657, 15605413). ClinVar contains an entry for this variant (Variation ID: 410929). This variant is not present in population databases (ExAC no frequency). - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 12, 2018 | The c.1960G>C pathogenic mutation (also known as p.V654L), located in coding exon 19 of the RB1 gene, results from a G to C substitution at nucleotide position 1960. The amino acid change results in valine to leucine at codon 654, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 19, which makes it likely to have some effect on normal mRNA splicing. This mutation has been described in multiple individuals with retinoblastoma (Alonso J et al. Hum. Mutat. 2005 Jan;25(1):99; Li T et al. Int J Clin Exp Pathol 2016;9(2):2120-2126; Ambry internal data). Using two different splice site prediction tools, this alteration is predicted by ESEfinder to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by BDGP. RNA studies using patient RNA have shown that both this alteration and another mutation at this nucleotide position (c.1960G>A) cause exon 19 skipping, resulting in a truncated protein (Houdayer C et al. Hum. Mutat. 2008 Jul;29(7):975-82). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at