ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.145T>A (p.Tyr49Asn) (rs764367878)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000469078 SCV000542169 uncertain significance Neurofibromatosis, type 1 2018-08-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 49 of the NF1 protein (p.Tyr49Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is present in population databases (rs764367878, ExAC 0.002%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 404570). 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: "Deleterious"; 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 RCV000681013 SCV000808462 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing This variant is denoted NF1 c.145T>A at the cDNA level, p.Tyr49Asn (Y49N) at the protein level, and results in the change of a Tyrosine to an Asparagine (TAC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Tyr49Asn 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 Tyrosine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. NF1 Tyr49Asn occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether NF1 Tyr49Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001011690 SCV001172040 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-27 criteria provided, single submitter clinical testing Insufficient evidence

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