ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.7491C>G (p.Ala2497=) (rs141897690)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163564 SCV000214122 likely benign Hereditary cancer-predisposing syndrome 2014-08-25 criteria provided, single submitter clinical testing Synonymous alterations with insufficient evidence to classify as benign
Invitae RCV001080554 SCV000284514 likely benign Neurofibromatosis, type 1 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000434650 SCV000533038 uncertain significance not provided 2017-05-31 criteria provided, single submitter clinical testing This variant is denoted NF1 c.7491C>G at the DNA level. This variant is silent at the coding level, preserving an Alanine at codon 2497. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. In silico splicing models are uninformative; therefore, in the absence of RNA or functional studies, the actual effect of this variant is unknown. NF1 c.7491C>G was observed at an allele frequency of 0.06% (6/10,390) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The nucleotide which is altered, a cytosine (C) at base 7491, is not conserved. Based on currently available information, it is unclear whether NF1 c.7491C>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780545 SCV000917891 benign not specified 2018-04-30 criteria provided, single submitter clinical testing Variant summary: NF1 c.7491C>G 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 observed variant frequency within African control individuals in the gnomAD database is approximately 3 fold above 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. To our knowledge, no occurrence of c.7491C>G in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285794 SCV001472280 likely benign none provided 2019-10-11 criteria provided, single submitter clinical testing

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