Submissions for variant NM_000321.3(RB1):c.1960G>A (p.Val654Met)

dbSNP: rs483352690

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001854505	SCV002121401	pathogenic	Retinoblastoma	2021-09-16	criteria provided, single submitter	clinical testing	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: 12541220, 15605413, 18181215, 21615945, 28606269). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 100808). This missense change has been observed in individual(s) with retinoblastoma (PMID: 14722923, 15884040, 22084214, 26925970, 29568217). It has also been observed in individuals without personal history of RB1-related conditions (PMID:29568217, 22084214, 26925970, 14722923). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 654 of the RB1 protein (p.Val654Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant also falls at the last nucleotide of exon 19, which is part of the consensus splice site for this exon.
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	RCV001854505	SCV005046227	pathogenic	Retinoblastoma	2024-05-20	criteria provided, single submitter	clinical testing	Case and Pedigree Information: BILATERAL CASES:0, UNILATERAL CASES:2, TOTAL CASES:2, PEDIGREES:1. ACMG Codes Applied:PVS1, PM2
Richard Lifton Laboratory, Yale University School of Medicine	RCV000087166	SCV000120028	unknown	not provided		flagged submission	not provided	Converted during submission to Uncertain significance.
Richard Lifton Laboratory, Yale University School of Medicine	RCV000087166	SCV000155131	probable-pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.