ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.5888A>G (p.Asn1963Ser) (rs764291252)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465912 SCV000542240 uncertain significance Neurofibromatosis, type 1 2019-11-16 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1963 of the NF1 protein (p.Asn1963Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs764291252, ExAC 0.01%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 404620). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000482669 SCV000570039 uncertain significance not provided 2016-04-18 criteria provided, single submitter clinical testing This variant is denoted NF1 c.5888A>G at the cDNA level, p.Asn1963Ser (N1963S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Asn1963Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. NF1 Asn1963Ser occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function (UniProt). Based on currently available evidence, it is unclear whether NF1 Asn1963Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000565316 SCV000663018 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-11 criteria provided, single submitter clinical testing Insufficient evidence

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