Submissions for variant NM_000321.3(RB1):c.1278_1279insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGCGGCGGGGCCGGCGGAAGAAGGCGGTGGCGGGGCCCTGCCCCGCTCCGGCTGTGGCGCGGCCCGCGCCCGTTCCAGGATACATCTTT (p.Lys427delinsPhePhePhePhePhePheXaaXaaXaaXaaAlaAlaGlyProAlaGluGluGlyGlyGlyGlyAlaLeuProArgSerGlyCysGlyAlaAlaArgAlaArgSerArgIleHisLeuTer)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002876067	SCV003232418	pathogenic	Retinoblastoma	2022-08-31	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 13 of the RB1 gene (c.1278_1279ins?), causing a frameshift at codon 427 (p.Lys427fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). For these reasons, this variant has been classified as Pathogenic.