ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1756_1759del (p.Thr586fs) (rs786202782)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165769 SCV000216514 pathogenic Hereditary cancer-predisposing syndrome 2015-11-12 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000467300 SCV000541963 pathogenic Neurofibromatosis, type 1 2019-11-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr586Valfs*18) in the NF1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with neurofibromatosis type 1 (PMID: 9783703, 25788518, 17311297, 18546366, 16835897). ClinVar contains an entry for this variant (Variation ID: 186215). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000484704 SCV000568603 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing The c.1756_1759delACTA variant has been reported previously in association with neurofibromatosis type 1 (Park et al., 1998). The deletion causes a frameshift starting with codon Threonine 586, changes this amino acid to a Valine residue and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Thr586ValfsX18. The c.1756_1759delACTA variant has been shown to result in lowered neurofibromin expression and increased RAS activity compared to wild type (Anastasaki et al., 2015). Additionally, the variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we consider this variant to be pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000467300 SCV000588376 pathogenic Neurofibromatosis, type 1 2017-06-18 criteria provided, single submitter clinical testing
Medical Genetics, University of Parma RCV000467300 SCV000588734 pathogenic Neurofibromatosis, type 1 2019-12-20 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000467300 SCV000781929 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000484704 SCV000842883 pathogenic not provided 2017-12-29 criteria provided, single submitter clinical testing
Department of Ophthalmology, Shanghai Ninth people hospital, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University RCV000787330 SCV000926272 pathogenic Neurofibroma 2019-06-29 no assertion criteria provided clinical testing

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