ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1845G>T (p.Lys615Asn) (rs1131691080)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492781 SCV000581265 pathogenic Hereditary cancer-predisposing syndrome 2015-01-08 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Last nucleotide of exon;Functionally-validated splicing mutation;Other acmg-defined mutation (i.e. initiation codon or gross deletion);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Significant disease association in appropriately sized case-control study(ies)
Invitae RCV000549833 SCV000628391 uncertain significance Neurofibromatosis, type 1 2017-04-16 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 615 of the NF1 protein (p.Lys615Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant also falls at the last nucleotide of exon 16 of the NF1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with a diagnosis or clinical suspicion of neurofibromatosis type 1 (NF1) (PMID: 1854636) and an individual with an atypical presentation of NF1 and ductal carcinoma in situ (PMID: 23322702). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare missense change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000680814 SCV000808261 likely pathogenic not provided 2018-04-13 criteria provided, single submitter clinical testing This variant is denoted NF1 c.1845G>T at the cDNA level. Located at the last nucleotide of exon 16, it disrupts a natural splice site and causes abnormal splicing. Studies have demonstrated that this variant results in skipping of exon 16 (referred to as exon 12a in published reports) and/or exons 15 and 16 (exons 11 and 12a) (Pros 2008, Sabbagh 2013). This variant has been observed in several individuals with neurofibromatosis type 1 (Pros 2008, Onitilo 2013, Sabbagh 2013, Duat Rodriguez 2015, Santoro 2017). Although the substitution results in the change of a Lysine to an Asparagine at codon 615 and is called p.Lys615Asn (K615N) in the literature, we are only using the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. NF1 c.1845G>T was not observed in large population cohorts (Lek 2016). In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider NF1 Lys615Asn to be a likely pathogenic variant.

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