ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4269G>C (p.Lys1423Asn) (rs199474750)

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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 RCV000492589 SCV000581313 likely pathogenic Hereditary cancer-predisposing syndrome 2016-04-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000467960 SCV000542063 pathogenic Neurofibromatosis, type 1 2018-06-06 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 1423 of the NF1 protein (p.Lys1423Asn). 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 31 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 observed in individuals with symptoms consistent with neurofibromatosis type 1 (NF1) (PMID: 18546366, Invitae). ClinVar contains an entry for this variant (Variation ID: 404485). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this sequence change disrupts mRNA splicing resulting in the partial or complete skipping of exon 31 (also known as exon 24) (PMID: 18546366). Variants that disrupt the p.Lys1423 amino acid residue in NF1 have been observed in affected individuals (PMID: 1568247, 8264648, 27322474). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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