ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1392+5_1392+6delinsTT (rs587782851)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132450 SCV000187544 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting benign classification
Invitae RCV000226320 SCV000284380 uncertain significance Neurofibromatosis, type 1 2019-12-27 criteria provided, single submitter clinical testing This sequence change falls in intron 12 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is reported as two separate single-nucleotide changes in population databases (c.1392+5G>T, ExAC <0.01% and c.1392+6A>T, ExAC <0.01%). However, in the read data for 5/5 individuals displayed in the ExAC browser, these two variants are in cis. This recapitulates the variant observed here (c.1392+5_1392+6delGAinsTT) and indicates that this variant is very likely present in the population databases at <0.01%. This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 142958). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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.
GeneDx RCV000413830 SCV000491544 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing This variant is denoted NF1 c.1392+5_1392+6delGAinsTT or IVS12+5_IVS12+6delGAinsTT. The normal sequence, with the bases that are deleted in braces and inserted in brackets, is gtaa[delga][instt]taaa. In silico models predict this variant to damage or destroy the nearby natural donor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. NF1 c.1392+5_1392+6delGAinsTT was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Variant Server, indicating it is not a common benign variant in these populations. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. The nucleotides that are deleted are conserved across species. Based on the currently available information, we consider NF1 c.1392+5_1392+6delGAinsTT to be a variant of uncertain significance.
PreventionGenetics,PreventionGenetics RCV000413830 SCV000806255 uncertain significance not provided 2017-06-21 criteria provided, single submitter clinical testing

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