ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2573C>G (p.Ser858Cys) (rs369493270)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164772 SCV000215448 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (benign)
Invitae RCV000475700 SCV000542004 uncertain significance Neurofibromatosis, type 1 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 858 of the NF1 protein (p.Ser858Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs369493270, ExAC 0.008%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 185364). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000681003 SCV000808452 uncertain significance not provided 2016-08-24 criteria provided, single submitter clinical testing This variant is denoted NF1 c.2573C>G at the cDNA level, p.Ser858Cys (S858C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Ser858Cys was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NF1 Ser858Cys occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether NF1 Ser858Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001027838 SCV001190458 uncertain significance Neurofibromatosis, familial spinal; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2019-01-16 criteria provided, single submitter clinical testing NF1 NM_000267.3 exon 21 p.Ser858Cys (c.2573C>G): This variant has not been reported in the literature and is present in 0.005% (6/113248) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/17-29556206-C-G). This variant is present in ClinVar (Variation ID:185364). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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