Submissions for variant NM_000267.3(NF1):c.4269G>A (p.Lys1423=) (rs199474750)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc	RCV000497159	SCV000782016	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000485227	SCV000573246	likely pathogenic	not provided	2017-02-24	criteria provided, single submitter	clinical testing	The c.4269 G>A (K1423K) variant has been published previously in association with neurofibromatosis type 1 (Sites et al., 2016). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). While the variant is a synonymous nucleotide change that does not alter the amino acid sequence, the variant occurs at a nucleotide that is conserved across species. In silico analysis predicts this variant destroys the natural splice donor site of intron 31. Additionally, cell lines containing this variant were able to form colonies and lost contact inhibition; they also showed the ability to form tumors when introduced to mice (Li et al., 2016). In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000497159	SCV000628581	uncertain significance	Neurofibromatosis, type 1	2017-06-11	criteria provided, single submitter	clinical testing	This sequence change affects codon 1423 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. 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. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with neurofibromatosis type 1 in the literature and in the Leiden Open-source Variation Database (PMID: 27862945, 28068329, 21520333). ClinVar contains an entry for this variant (Variation ID: 423536). 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. A different variant affecting this nucleotide (c.4269G>C) has been determined to be pathogenic (PMID: 18546366, Invitae). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. In summary, this variant has uncertain impact on NF1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Medical Genetics,University of Parma	RCV000497159	SCV000588779	uncertain significance	Neurofibromatosis, type 1	2017-02-02	no assertion criteria provided	clinical testing