ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2985G>C (p.Leu995=) (rs17881467)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000680362 SCV000885832 benign not provided 2017-10-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163174 SCV000213695 benign Hereditary cancer-predisposing syndrome 2014-11-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
GeneDx RCV000680362 SCV000531131 likely benign not provided 2018-04-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000222166 SCV000919886 benign not specified 2018-09-07 criteria provided, single submitter clinical testing Variant summary: NF1 c.2985G>C alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Two predict the variant no significant impact on splicing. Two predict the variant abolishes a cryptic 5 donor site. One predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0012 in 276472 control chromosomes, predominantly within the African subpopulation at a frequency of 0.013 in the gnomAD database, including 1 homozygote. This frequency within African control individuals is approximately 62-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.2985G>C in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another likely pathogenic variant has been identified by our laboratory (BRIP1 c.1474-1G>A), providing supporting evidence for a benign role. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000204155 SCV000262434 benign Neurofibromatosis, type 1 2018-01-09 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000222166 SCV000269452 benign not specified 2014-11-24 criteria provided, single submitter clinical testing Leu995Leu in exon 22 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 1.2% (52/4404) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17881467).
PreventionGenetics RCV000222166 SCV000306252 benign not specified criteria provided, single submitter clinical testing

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