Submissions for variant NM_000321.3(RB1):c.34_36dup (p.Thr12_Ala13insThr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002452071	SCV002612649	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-20	criteria provided, single submitter	clinical testing	The c.34_36dupACC variant (also known as p.T12dup), located in coding exon 1 of the RB1 gene, results from an in-frame duplication of ACC at nucleotide positions 34 to 36. This results in the duplication of an extra threonine residue between codons 12 and 13. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003108013	SCV003783428	uncertain significance	Retinoblastoma	2023-11-13	criteria provided, single submitter	clinical testing	This variant, c.34_36dup, results in the insertion of 1 amino acid(s) of the RB1 protein (p.Thr12dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1731062). 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	RCV003108013	SCV004846293	uncertain significance	Retinoblastoma	2023-12-01	criteria provided, single submitter	clinical testing	This variant causes a duplication of threonine at amino acid 12 of the RB1 protein. 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 2/135924 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.