ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3436G>A (p.Val1146Ile) (rs201047812)

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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 RCV000129967 SCV000184791 likely benign Hereditary cancer-predisposing syndrome 2015-12-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: in silico models in agreement (benign),Does not segregate with disease in family study (genes with incomplete penetrance),Other data supporting benign classification
Invitae RCV000200527 SCV000254494 uncertain significance Neurofibromatosis, type 1 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1146 of the NF1 protein (p.Val1146Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs201047812, ExAC 0.02%). This variant has been reported in an individual affected with neurofibromatosis type 1 (PMID: 16138229). ClinVar contains an entry for this variant (Variation ID: 141451). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000612512 SCV000711646 uncertain significance not specified 2016-08-11 criteria provided, single submitter clinical testing The p.Val1164Ile variant in NF1 has been reported in 3 individuals with Neurofib romatosis type 1 (NF1; Trovo 2004, Mendelian Genes). This variant has also been identified in 11/66714 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201047812). An additional amino a cid change at this position (p.Val1164 Phe) has been reported to occur de novo i n two individuals with NF1 (Mendelian Genes), suggesting that a change at this p osition may not be tolerated. However, valine (Val) at position 1146 is not cons erved in evolutionary distant species, with multiple fish species carrying an is oleucine (Ile) at this position, and raising the possibility that a change at th is position may be tolerated. Additional computational prediction tools suggest that the p.Val1146Ile variant may not impact the protein, though this informatio n is not predictive enough to rule out pathogenicity. In summary, due to conflic ting data, the clinical significance of the p.Val1146Ile variant is uncertain.
GeneKor MSA RCV000129967 SCV000822095 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000200527 SCV000839142 uncertain significance Neurofibromatosis, type 1 2018-07-02 criteria provided, single submitter clinical testing

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