ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3883A>G (p.Thr1295Ala) (rs143836226)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165261 SCV000215977 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000205468 SCV000260388 uncertain significance Neurofibromatosis, type 1 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1295 of the NF1 protein (p.Thr1295Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs143836226, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 185777). 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 and their clinical significance is uncertain. 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.
GeneDx RCV000680330 SCV000518631 likely benign not provided 2018-01-25 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Fulgent Genetics,Fulgent Genetics RCV000515307 SCV000611411 uncertain significance Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2017-05-23 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000428670 SCV000712065 uncertain significance not specified 2016-11-03 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr1295Ala va riant in NF1 has been identified in 1 individual with clinical features of a RAS opathy disorder, but was inherited from an unaffected parent. It has been identi fied in 10/66730 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143836226). Computational prediction to ols and conservation analysis suggest that the p.Thr1295Ala variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. In summary, while the clinical significance of the p.Thr1295Ala vari ant is uncertain, these data suggest that it is more likely to be benign.
GeneKor MSA RCV000165261 SCV000822096 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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