ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.586G>A (p.Glu196Lys) (rs876659079)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222660 SCV000275112 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000468972 SCV000541983 uncertain significance Neurofibromatosis, type 1 2016-10-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 196 of the NF1 protein (p.Glu196Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is also located within a consensus splice site since it falls at the last nucleotide of exon 5 of the NF1 coding sequence. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 231304). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098) but according to multiple splice site algorithms this particular variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published functional studies. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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