ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.6365-3C>T (rs374014162)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164785 SCV000215463 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000228132 SCV000284495 uncertain significance Neurofibromatosis, type 1 2019-12-02 criteria provided, single submitter clinical testing This sequence change falls in intron 41 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 present in population databases (rs374014162, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with NF1-related disease. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000444313 SCV000511104 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
GeneDx RCV000444313 SCV000808479 uncertain significance not provided 2018-01-29 criteria provided, single submitter clinical testing This variant is denoted NF1 c.6365-3C>T or IVS41-3C>T and consists of a C>T nucleotide substitution at the -3 position of intron 41 of the NF1 gene. This variant has been identified in at least two individuals with a diagnosis or clinical suspicion of Neurofibromatosis Type 1 (Wimmer 2007, Pros 2008). While in silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function, RT-PCR analysis suggested this variant results in an out-of-frame deletion of exon 42 (previously reported as exon 34), but the data were not provided (Wimmer 2007, Pros 2008). This variant was observed at an allele frequency of 0.01% (16/126,474) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether NF1 c.6365-3C>T is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780541 SCV000917884 uncertain significance not specified 2018-01-08 criteria provided, single submitter clinical testing Variant summary: The NF1 c.6365-3C>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict a non-significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 17/276834 control chromosomes at a frequency of 0.0000614, which does not exceed the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084). The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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