Submissions for variant NM_000321.3(RB1):c.2091C>G (p.Asp697Glu)

gnomAD frequency: 0.00001  dbSNP: rs3092903

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000306444	SCV000384554	uncertain significance	Retinoblastoma	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000306444	SCV000629298	likely benign	Retinoblastoma	2025-01-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001014403	SCV001175103	benign	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV002305481	SCV002599720	uncertain significance	not provided	2022-11-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29625052, 15776430, 27535533, Dono2021[CaseReport], Dayalan_2006_Review)
Baylor Genetics	RCV003463782	SCV004208489	uncertain significance	Malignant tumor of urinary bladder	2023-10-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000306444	SCV004844720	uncertain significance	Retinoblastoma	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 697 of the RB1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with retinoblastoma in the literature, but has been observed in an unaffected individual (PMID: 15776430). This variant has been identified in 4/251480 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.