ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.5295G>A (p.Ser1765=) (rs373313111)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482095 SCV000573849 uncertain significance not provided 2017-03-06 criteria provided, single submitter clinical testing The c.5295 G>A (S1765S) variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). While c.5295 G>A is a synonymous variant and would not result in a change to the amino acid sequence, several in-silico splice prediction models predict that the variant creates a cryptic acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics RCV000571061 SCV000674075 likely benign Hereditary cancer-predisposing syndrome 2016-04-18 criteria provided, single submitter clinical testing Synonymous alterations with insufficient evidence to classify as benign
Invitae RCV000632315 SCV000753492 uncertain significance Neurofibromatosis, type 1 2018-08-29 criteria provided, single submitter clinical testing This sequence change affects codon 1765 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. This variant is present in population databases (rs373313111, ExAC 0.001%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 424072). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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