Submissions for variant NM_000321.3(RB1):c.1160T>C (p.Met387Thr)

dbSNP: rs767908749

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001234074	SCV001406700	uncertain significance	Retinoblastoma	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 387 of the RB1 protein (p.Met387Thr). This variant is present in population databases (rs767908749, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 960531). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function with a negative predictive value of 80%. 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.
All of Us Research Program, National Institutes of Health	RCV001234074	SCV004827635	uncertain significance	Retinoblastoma	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 387 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 been identified in 1/250730 chromosomes 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.
Baylor Genetics	RCV004570589	SCV005054124	uncertain significance	Malignant tumor of urinary bladder	2024-02-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004671283	SCV005160483	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-03	criteria provided, single submitter	clinical testing	The p.M387T variant (also known as c.1160T>C), located in coding exon 12 of the RB1 gene, results from a T to C substitution at nucleotide position 1160. The methionine at codon 387 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. 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.