ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.2553C>T (p.Cys851=)

gnomAD frequency: 0.00190  dbSNP: rs2230852
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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 RCV000130541 SCV000185410 benign Hereditary cancer-predisposing syndrome 2014-12-01 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV001084162 SCV000252679 benign Neurofibromatosis, type 1 2020-11-23 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000217841 SCV000269451 benign not specified 2014-11-24 criteria provided, single submitter clinical testing Cys851Cys in exon 21 of NF1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 0.7% (33/4406) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (; dbSNP rs2230852).
GeneDx RCV000680357 SCV000529105 likely benign not provided 2021-02-05 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000217841 SCV000595971 likely benign not specified 2016-07-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000217841 SCV000919884 benign not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: NF1 c.2553C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00053 in 276370 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0054 in the gnomAD database, including 1 homozygote. The observed variant frequency within African control individuals in the gnomAD database is approximately 26 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. However, the region is highly homologous to pseudogenes, and the technology utilized for this dataset does not rule out pseudogene interference making ExAC and gnomAD data unreliable for assessing variant frequency. To our knowledge, no occurrence of c.2553C>T in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as Benign.
Genome Diagnostics Laboratory,The Hospital for Sick Children RCV001084162 SCV001478988 benign Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000130541 SCV002527464 benign Hereditary cancer-predisposing syndrome 2020-09-19 criteria provided, single submitter curation
Genome-Nilou Lab RCV001084162 SCV002560211 benign Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing

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