ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1466A>G (p.Tyr489Cys) (rs137854557)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757556 SCV000885830 pathogenic not provided 2017-07-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000492667 SCV000581253 pathogenic Hereditary cancer-predisposing syndrome 2014-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000000382 SCV000678216 pathogenic Neurofibromatosis, type 1 2017-08-01 criteria provided, single submitter clinical testing NF1 NM_001042492.2 exon1 p.Tyr489Cys (c.1466A>G): This variant has been reported in >10 individuals with Neurofibromatosis type 1 (NF1), including 1 individual in which this variant was de novo (Messiaen 1999 PMID: 11258625, Ars 2000 PMID:10607834, Messiaen 2000 PMID:10862084, Bongiomo 2008 PMID:19076627, Laycock-van Spyk 2011 PMID:22155606, Ribeiro 2012 PMID:22190595, Laurito 2015 PMID:25919870, Zhang 2015 PMID:26056819). This variant segregated with disease in 2 affected family members (Ars 2000 PMID:10607834). This variant is present in 3/245628 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs137854557). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar (Variation ID:354). Evolutionary conservation and computational predictive tools for this variant are unclear. Of note, functional studies have shown a deleterious effect of this variant, resulting in the creation of a new splice site (Messiaen 1999 PMID: 11258625, Ars 2000 PMID:10607834, Messiaen 2000 PMID:10862084). In summary, this variant is classified as pathogenic based on the data above (presence of this variant in affected probands, presence as a de novo and predicted impact to protein).
Center for Human Genetics, Inc RCV000000382 SCV000781908 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000000382 SCV000218980 pathogenic Neurofibromatosis, type 1 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 489 of the NF1 protein (p.Tyr489Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. The frequency data for this variant (rs137854557) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in multiple individuals affected with neurofibromatosis type 1. It is a recurrent mutation that accounts for as many as 2% of neurofibromatosis type 1 causative alleles (PMID: 11258625, 10607834, 10862084, 10543400, 22155606, 22190595, 19076627). ClinVar contains an entry for this variant (Variation ID: 354). Experimental studies have shown that this sequence change affects splicing and causes skipping of 62 nucleotides in exon 13 (referred to as exon 10b in the literature). This is expected to alter the reading frame of NF1 and lead to an absent or disrupted protein (PMID: 11258625, 10543400, 10607834). For these reasons, this sequence change has been classified as Pathogenic.
Medical Genetics,University of Parma RCV000000382 SCV000588721 uncertain significance Neurofibromatosis, type 1 2017-02-02 no assertion criteria provided clinical testing
OMIM RCV000000382 SCV000020526 pathogenic Neurofibromatosis, type 1 2003-02-01 no assertion criteria provided literature only

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