Submissions for variant NM_000321.3(RB1):c.130C>G (p.Leu44Val)

dbSNP: rs1345893304

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001362751	SCV001558784	uncertain significance	Retinoblastoma	2021-04-02	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with RB1-related conditions. 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. 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 leucine with valine at codon 44 of the RB1 protein (p.Leu44Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine.
Baylor Genetics	RCV003469598	SCV004208500	uncertain significance	Malignant tumor of urinary bladder	2023-09-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001362751	SCV004836953	uncertain significance	Retinoblastoma	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 44 of the RB1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RB1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004656559	SCV005160497	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-04	criteria provided, single submitter	clinical testing	The p.L44V variant (also known as c.130C>G), located in coding exon 1 of the RB1 gene, results from a C to G substitution at nucleotide position 130. The leucine at codon 44 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.