ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3046T>C (p.Cys1016Arg)

dbSNP: rs878853880
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000229259 SCV000284424 pathogenic Neurofibromatosis, type 1 2024-06-06 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1016 of the NF1 protein (p.Cys1016Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NF1-related conditions (PMID: 19665063, 25541118; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 237543). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000229259 SCV000781970 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000229259 SCV002561827 pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV004992101 SCV005454579 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2024-08-11 criteria provided, single submitter clinical testing The p.C1016R variant (also known as c.3046T>C), located in coding exon 23 of the NF1 gene, results from a T to C substitution at nucleotide position 3046. The cysteine at codon 1016 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with features consistent with Neurofibromatous type I (Fauth C et al. Eur J Med Genet, 2009 Aug;52:409-14; Demir Gündoan B et al. Turk J Med Sci, 2021 Aug; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

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