ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.5450C>G (p.Ser1817Cys) (rs368654378)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132225 SCV000187308 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000168027 SCV000218679 uncertain significance Neurofibromatosis, type 1 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 1817 of the NF1 protein (p.Ser1817Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs368654378, ExAC 0.01%). This variant has been reported in an individual with neurofibromatosis type 1 (PMID: 27322474). ClinVar contains an entry for this variant (Variation ID: 142804). 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 RCV000484858 SCV000572284 uncertain significance not provided 2018-09-27 criteria provided, single submitter clinical testing This variant is denoted NF1 c.5450C>G at the cDNA level, p.Ser1817Cys (S1817C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant, also reported as p.Ser1838Cys using alternate nomenclature, was observed in at least one individual meeting the diagnostic criteria for Neurofibromatosis Type 1 (NF1) and has also been observed in an individual with liposarcoma (Ballinger 2016, Evans 2016). NF1 Ser1817Cys was observed at an allele frequency of 0.02% (23/126,618) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Ser1817Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000515448 SCV000611412 uncertain significance Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2017-05-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000484858 SCV000806297 uncertain significance not provided 2017-05-09 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001128217 SCV001287631 uncertain significance Café-au-lait macules with pulmonary stenosis 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001128218 SCV001287632 likely benign Neurofibromatosis-Noonan syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001128219 SCV001287633 uncertain significance Neurofibromatosis, familial spinal 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000168027 SCV001287634 uncertain significance Neurofibromatosis, type 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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