ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.6172A>G (p.Ile2058Val)

gnomAD frequency: 0.00017  dbSNP: rs201712827
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130497 SCV000185366 likely benign Hereditary cancer-predisposing syndrome 2015-06-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000205125 SCV000262159 uncertain significance Neurofibromatosis, type 1 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2037 of the NF1 protein (p.Ile2037Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs201712827, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 134887). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly 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.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000121636 SCV000731960 uncertain significance not specified 2017-09-19 criteria provided, single submitter clinical testing The p.Ile2058Val variant in NF1 has not been previously reported in individuals with RASopathies, but has been reported in ClinVar (Variation ID: 134887). It ha s been identified in 22/125856 European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201712827). Computatio nal prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of t he p.Ile2058Val variant is uncertain.
Mendelics RCV000205125 SCV001140387 uncertain significance Neurofibromatosis, type 1 2019-05-28 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000205125 SCV001367524 uncertain significance Neurofibromatosis, type 1 2019-02-20 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
GeneDx RCV001588968 SCV001815315 likely benign not provided 2019-04-30 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 32107864, 24728327)
Genetic Services Laboratory,University of Chicago RCV000121636 SCV002071889 uncertain significance not specified 2020-12-24 criteria provided, single submitter clinical testing DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.6109A>G, in exon 41 that results in an amino acid change, p.Ile2037Val. This sequence change does not appear to have been previously described in patients with NF1-related disorders and has been described in the gnomAD database with a low population frequency of 0.016% in non-Finnish European subpopulation (dbSNP rs201712827). The p.Ile2037Val change affects a moderately conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile2037Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile2037Val change remains unknown at this time.
Institute of Human Genetics, University of Leipzig Medical Center RCV000205125 SCV002505549 uncertain significance Neurofibromatosis, type 1 2022-04-28 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PP2
Sema4,Sema4 RCV000130497 SCV002527643 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-08 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121636 SCV002556259 likely benign not specified 2022-06-30 criteria provided, single submitter clinical testing Variant summary: NF1 c.6109A>G (p.Ile2037Val) results in a conservative amino acid change which is located outside of any known functional domain or repeat of the encoded protein sequence (InterPro, UniProt). Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250150 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.00021), allowing no conclusion about variant significance. However, the variant is reported with a much higher occurrence in the Amish (i.e. 11/910 alleles; a frequency of 0.012), suggesting that the variant might be a benign polymorphism. The variant, c.6109A>G, has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (Koczkowska_2018) or suspected RASopathy (Witkowski_2020), however in one of these reports the variant was found in a family in the proband, and not found in two affected family members, while all affected family members had a (likely) pathogenic variant, which segregated with the disease phenotype (Koczkowska_2018). In addition, the variant was reported in patients with breast cancer (Dorling_2021), but was also found in healthy controls (Bodian_2014, Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=8) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
ITMI RCV000121636 SCV000085834 not provided not specified 2013-09-19 no assertion provided reference population
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000130497 SCV001977050 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-27 no assertion criteria provided clinical testing

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