ClinVar Miner

Submissions for variant NM_000321.2(RB1):c.1268G>A (p.Gly423Glu) (rs748635133)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480107 SCV000570797 uncertain significance not provided 2016-06-30 criteria provided, single submitter clinical testing This variant is denoted RB1 c.1268G>A at the cDNA level, p.Gly423Glu (G423E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RB1 Gly423Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RB1 Gly423Glu occurs at a position that is not conserved and is located in domain A of the Pocket region (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether RB1 Gly423Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000531874 SCV000629274 uncertain significance Retinoblastoma 2017-04-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 423 of the RB1 protein (p.Gly423Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs748635133, ExAC 0.001%) but has not been reported in the literature in individuals with a RB1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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